Regioselective Synthesis of 1,5-Disubstituted 1,2,3-Triazoles by Reusable AlCl3 Immobilized on γ-Al2O3

Article abstract of DOI:10.1080/00397911.2014.997366

(Chemical Equation Presented) There is rapidly growing interest in the synthesis and use of substituted 1,2,3-triazoles. We report an easy and interesting procedure that demonstrates the effectiveness of surface-modified γ-Al₂O₃, which is reusable, efficient, catalytic, safe, and environmentally acceptable for the regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles via [3 + 2] cycloaddition of phenyl and benzyl azides with a series of aryl nitroolefins in good yields. No adverse effect on substituents such as nitro, cyano, hydroxy, ether linkage, and halogens was observed. The catalyst could easily be recycled and was reused for nine runs without losing its activity.

Full text of DOI:10.1080/00397911.2014.997366

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Regioselective Synthesis of 1,5-Disubstituted 1,2,3-
Triazoles by Reusable Immobilized AlCl3 on γ-Al2O3
Hemmaragala M. Nanjundaswamya & Heidi Abrahamsea
a Laser Research Centre, Faculty of Health Sciences, University of Johannesburg,
Doornfontein, South Africa
Accepted author version posted online: 31 Dec 2014.
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To cite this article: Hemmaragala M. Nanjundaswamy & Heidi Abrahamse (2014): Regioselective Synthesis of 1,5-Disubstituted
1,2,3-Triazoles by Reusable Immobilized AlCl3 on γ-Al2O3, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.997366
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Regioselective Synthesis of 1,5-Disubstituted 1,2,3-Triazoles by reusable immobilized
AlCl3 on γ-Al2O3
Hemmaragala M. Nanjundaswamy1, Heidi Abrahamse1
1Laser Research Centre, Faculty of Health Sciences, University of Johannesburg,
Doornfontein, South Africa
Corresponding author Hemmaragala M. Nanjundaswamy Address: Laser Research
Centre, Faculty of Health Sciences, University of Johannesburg, P. O. Box 17011,
Doornfontein 2028, South Africa E-mail: nswamyorg@gmail.com
Abstract
There is rapidly growing interest in the synthesis and use of substituted 1,2,3-triazoles.
We report the easy and interesting procedure demonstrating the effectiveness of the
surface modified γ-Al2O3 which is reusable, efficient, catalytic, safe and environmentally
acceptable for the regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles via [3+2]
cycloaddition of phenyl and benzyl azides with a series of aryl nitroolefins in good
yields. No adverse effect on substituents such as nitro, cyano, hydroxy, ether linkage and
halogens was observed. The catalyst could easily be recycled and was reused nine runs
without losing its activity.
KEYWORDS: 1,5-disubstituted-1,2,3-triazoles; Immobilized AlCl3 on γ-Al2O3; [3+2]
cycloaddition; nitroolefins; azide
1

INTRODUCTION
The 1,2,3-Triazole family exhibit a broad spectra of bio-activities such as antifungal,[1]
antiviral,[2] antibacterial[3] and anticancer activities.[4] 1,2,3-triazoles and the derivatives
have been the current interest of research owing to their importance in contribution to the
development of new drugs candidates.[5] The 1,2,3-triazole derivative of cyclopentenyl
carbocyclic nucleosides 1 has been demonstrated to be a potent antiviral agent against
orthopoxviruses and SARS.[6] 1,2,3-triazole moiety is been manipulated with zanamivir
derivatives 2 and are studied for their anti-AIV activities[7] and 3-arylethylnyltriazolyl
ribonucleosides have been studied for successful anticancer activity on the drug-resistant
pancreatic cancer cell line MiaPaca-2.[8] Very recently, 1,2,3-triazoles attached with
heterocyclic fragments 3 have been screened and found to active against melanoma,
colon and breast cancer.[9]
AlCl3 is one of the prime members of Friedel-Craft’s catalysts that are widely used in
petroleum refining and pharmaceutical industries. AlCl3 plays a major role in alkylation,
acylation, alkene isomerization, cracking, and polymerization processes. It should be
noted that researchers of late, avoid using AlCl3 because of drawbacks such as its
corrosiveness, difficulty in separating the used/unreacted catalyst from products, and
production of a large amount of waste. A promising improvement of traditional AlCl3
catalysts is the immobilization of AlCl3 on a support. Immobilization of AlCl3 can easily
be achieved on supports such as Al2O3, SiO2, etc.
2

In the year 1961, Rolf Huisgen demonstrated the synthesis of 1,2,3-triazoles by 1,3-
dipolar cycloaddition of azides and alkynes.[10] The Huisgen’s reaction is generally
carried out at elevated temperatures and unfortunately the reaction often produces a
mixture of 1,4- and 1,5-disubstituted mixtures and there is was a lack of regioselectivity.
Several modifications for Huisgen’s reaction to achieve 1,4- disubstituted-1,2,3-
triazoles[11-13] and 1,5-disubstituted 1,2,3-triazoles[14,15] have been reported using a variety
of metals mediated catalysts. Sasaki et al. have also demonstrated the regioselective
syntheses of adamantane derivatives of 1,2,3-triazoles via 1,3-dipolar cycloaddition
reactions.[16] Ce(OTf)3 is recently been employed to catalyze the cycloaddition to
achieve 1,5-disubstituted-1,2,3-triazoles in excellent yields,[17] we are dedicated in
making the route green and inexpensive and easy access to 1,5-disubstituted-1,2,3-
triazoles.
RESULTS AND DISCUSSION
In view of importance of 1,5-disubstituted-1,2,3-triazoles, we wanted to synthesize these
compounds using easily available inexpensive, reusable catalyst and we set out the
experiments to use immobilized AlCl3 on γ-Al2O3[18] and succeeded. Initially the
cycloaddition of terminal acetylenes and azides were tried and did not observe any trace
of the corresponding product with the range of polar and non-polar solvents such as
3

MeOH, DCM, DCE, EtOH, MeCN, DMSO, DMF, THF, benzene and toluene even at
elevated temperatures. When the acetylenes were replaced by (2-Nitroethenyl)benzene,
surprisingly we could able to get the desired product as shown in Scheme 1.
(2-Nitroethenyl)benzene (1b) afforded 56% (1C) in 12 hours and other substituted (2-
Nitroethenyl)benzenes with both phenyl and benzyl azides gave the desired 1,5-
Diphenyl-1H-1,2,3-triazoles at 100°C without any side reactions. The reaction of electron
withdrawing nitro and chloro substituents to (2-Nitroethenyl)benzene 10b, 11b and 13b
with benzyl azides afforded the products 10c 11c and 13c in maximum yields 82%, 79%
and 78% respectively with lesser time compared to other examples. It is worth noting
that, while the reaction of 1b, 4b and 8b with azides gave lower yields (56%, 58% and
57%) of the corresponding products, longer time was required to complete the reaction
between (2-Nitroethenyl)thiophene with both phenyl and benzyl azides. In case of the
reaction between 4-cyano-(2-Nitroethenyl)benzene (Entry 12) and benzyl cyanide, the
mixture of products 4-(1-Benzyl-1H-1,2,3-triazol-5-yl)Benzonitrile and 4-(1-Benzyl-1H-
1,2,3-triazol-5-yl)[5'-Phenyl-1'H-1',2',3',4'-tetrazole] were expected but, we could only
able to isolate 4-(1-Benzyl-1H-1,2,3-triazol-5-yl)Benzonitrile in 34%. Further, the
reaction of phenyl azide with (2-Nitroethenyl)benzene was chosen to survey the
efficiency of the catalyst and to standardize the amounts of catalyst to be employed and it
was found that 40 mg is enough to complete the reaction to obtain maximum yield.
Results of a range of amounts of immobilized catalyst are shown in Table 1; in the
absence of catalyst we could not isolate any product.
4

CONCLUSION
In summary, we have demonstrated an elegant method for the synthesis of a wide variety
of 1,5-disubstituted-1,2,3-triazoles in the presence of immobilized AlCl3 on γ-Al2O3. The
products of this environmentally friendly procedure, that allowed reuse of the catalyst,
were analytically pure. In addition, this reaction is convenient, affording good yields and
therefore we believe the procedure is very versatile and will increase the accessibility of
1,5-disubstituted-1,2,3-triazoles to the synthetic chemistry and biology community.
Experimental
Nitroolefins are prepared according to the previous report [19] and purified, all other
solvents were of analytical grade and purified wherever necessary according to standard
procedures prior to use. TLC was run on pre-coated silica gel on aluminium plates
obtained from Whatmann Inc. All reactions were performed at 100 ºC. Melting points
were obtained with Büchi B-540 apparatus. IR spectra were recorded on Bruker-
TENSOR-FTIR spectroscopy. 1H NMR and 13C NMR spectra were recorded on Bruker
Avance 400 and 100 MHz spectrometer respectively, chemical shifts were reported in
(ppm) with TMS as internal standard. Elemental analyses were performed on Perkin
Elmer – 2004. Yields refer to the isolated products after purification by column
chromatography using 70–230 mesh silica gel.
Typical Procedure To The Preparation Of Azides
In a typical experiment, (2-Nitroethenyl)benzene (150 mg, 1.0 mmol) is taken in to 10
mL round bottomed flask, 5 mL of toluene, phenyl azide (155 mg, 1.3 equiv.) were added
5

and started stirring meanwhile, immobilized AlCl3 on γ-Al2O3 (40 mg) is added into the
reaction flask and the mixture is gradually heated and maintained the temperature at 100
°C, after 12 h, the disappearance of starting material (2-Nitroethenyl)benzene was
observed on thin layer chromatography, the mixture was cooled, filtered and the catalyst
was removed off and preserved for recycling. The filtrate was evaporated off under
reduced pressure to get the crude which was purified by column chromatography over
silica gel using eluent (1.5: 8.5 :: ethyl acetate: hexane) to afford 124 mg (56% yield) of
pure 1,5-Diphenyl-1H-1,2,3-triazole (entry 1c) as white solid which melted at 113−114
°C (lit. 113−114 °C)[20]; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.47−7.41 (m, 3H),
7.40−7.32 (m, 5H), 7.24−7.21 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 137.7, 136.6,
133.4, 129.4, 129.2, 128.9, 128.6, 126.8, 125.2 ppm.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
Authors are grateful to the University of Johannesburg for the financial assistance.
Full experimental details, procedures for the preparation of 1,5-Diphenyl-1H-1,2,3-
triazoles, preparation of azides, preparation of catalyst, recycling of the spent catalyst,
1
physical constants, copies of H NMR, 13C NMR and the data can be found via the
“supplementary content” section of the article’s web page.
6

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9

Table 1 Results of the amounts of immobilized AlCl3 on γ-Al2O3 at 100 °Ca
Entry Catalyst (mg) Reaction time (h) Yield (%)
1
No catalyst
100
18
18
18
12
12
12
12
12
12
12
trace
6
2
10
20
30
40
50
60
70
80
90
100
4
15
41
56
56
56
56
56
56
56
6
7
8
9
10
11
12
13
aReaction of 1 mmol of (2-Nitroethenyl)benzene with 1.1 mmol of phenyl azide in 5 mL
of toluene at 100 °C in presence of various quantities of immobilized AlCl3 on γ-Al2O3.
10

Table 2 Immobilized AlCl3 on Al2O3 catalyzed synthesis of 1,5-disubstituted-1,2,3-
triazoles by the reaction of nitroolefins and azides in toluene at 100 ˚C
Entr Azide
Nitrolefin
Reactio Product (h)
Yield
a (%)
56
y
1
n time
12
2
3
12
10
61
70
4
5
10
14
58
62
11

6
7
9
9
73
67
8
9
57
9
9
8
63
82
10
11
8
79
12

12
9
34
13
8
78
64
14
10
aIsolated yields after column purification
13

Scheme 1.
14