A novel 'domino-click approach' to unsymmetrical Bis-1H-1,2,3-triazoles

Article abstract of DOI:10.1002/hlca.200790242

Aryl azides 1 were treated with allenylmagnesium bromide (2) to generate 1,5-disubstituted butynyl-1H-1,2,3-triazoles 3 in a domino fashion, which upon Cu^I-catalyzed 1,3-dipolar cycloaddition with aryl azides 4 afforded novel bis-1H-1,2,3-triaz

Full text of DOI:10.1002/hlca.200790242

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A Novel ꢀDomino-Click Approachꢁ to Unsymmetrical Bis-1H-1,2,3-triazoles
by AbidH. Banday a), Bhupinder S. Aroraa), MohammedS. Alam b), and
Halmuthur M. Sampath Kumar*a)
a) Synthetic Chemistry Division, Indian Institute of Integrative Medicine, Canal Road,
Jammu-Tawi 180001, India (fax: 0191-2569333; e-mail: hmskumar@yahoo.com)
b) Department of Chemistry, Jamia Hamdard University, New Delhi-110062, India
Aryl azides 1 were treated with allenylmagnesium bromide (2) to generate 1,5-disubstituted butynyl-
1H-1,2,3-triazoles 3 in a domino fashion, which upon CuI-catalyzed 1,3-dipolar cycloaddition with aryl
azides 4 afforded novel bis-1H-1,2,3-triazoles 5 in quantitative yields (Scheme 1 and Table).
Introduction. – Nitrogen-containing compounds are part of the basis of life and
constitute a major class of pharmacologically active compounds [1]. Amongst these, a
large number of 1H-1,2,3-triazoles and their derivatives attracted considerable
attention for the past few decades due to their chemotherapeutical value. Many 1H-
1,2,3-triazoles, including bis-triazoles, are found to be potent antimicrobial, analgesic,
anti-inflammatory, local-anesthetic, anticonvulsant, antineoplastic, antimalarial, and
antiviral agents [2]. Some of them exhibited antiproliferative, anticancer activity, and
several are used as DNA-cleaving agents and potassium-channel activators. Such
diverse biological functions are also reported for a variety of bis-triazoles. The ꢀclick
chemistryꢁ approach has been the most widely used method for the synthesis of libraries
of a large number of biologically active molecular frameworks, particularly for the
regioselective synthesis of 1H-1,2,3-triazoles, which involves the copper(I)-catalyzed
cycloaddition reaction between azides and terminal alkynes (CuAAC). This reaction
has been termed the ꢀcream of the cropꢁ of ꢀclick reactionsꢁ and has found application in
various facets of drug discovery as it enables a modular approach to generate novel
pharmacophores utilizing a collection of reliable chemical reactions [3]. Thus, the
development of the copper(I)-catalyzed ꢀtriazole click chemistryꢁ has led to many
interesting applications in synthetic and medicinal chemistry, molecular biology, and
material science. The bioorthogonality of azide and alkynes [4] has allowed the use of
their [3 þ 2] cycloaddition in various biological applications including target-guided
synthesis [5] and activity-based protein profiling [6]. Of particular interest would be the
dimeric heterocycle-based ligands which are designed for specific target interactions.
Various approaches reported for the synthesis of biologically relevant bis-triazoles
include the CuI-catalyzed 1,3-dipolar cycloaddition of monoazides with diacetylenes or
that of monoacetylenes with diazides. For example, the synthesis of bis-triazoles is
reported by the reactions of bis(azidomethyl)benzenes with several substituted
acetylenes [7]. Recently, due attention has been paid towards the synthesis and
pharmacological evaluation of triazoles and bis-triazoles as potent HIV-1protease
inhibitors [8] and size-specific ligands for mRNA hairpin loops [9], respectively.
ꢂ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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Results andDiscussions. – The wide range of pharmacological activities and
application potential [5][10] of triazole and bis-triazole systems prompted us to design
the synthesis of a library of unsymmetrical bis-1H-1,2,3-triazoles 5 based on a stepwise
synthetic route involving domino addition of allenylmagnesium bromide (2) to aryl
azides 1 resulting in a serendipitous formation of 5-butynylated triazoles 3 in good
yields (> 70%) instead of 4-butynylated triazoles (Scheme 1). The 5-butynylated
triazoles upon CuI-catalyzed 1,3-dipolar cycloaddition with aryl azides 4 (ꢀclick
reactionꢁ) generated bis-1H-1,2,3-triazoles 5 in quantitative yields, which were isolated
in pure form after precipitation (Table). The products together with the approach for
their synthesis being novel, the intermediate 5-butynylated triazoles 3 and the final
1
products, the bis-triazoles 5, were characterized by IR, H- and 13C-NMR, and MS
analysis.
Scheme 1
A plausible mechanisms for the formation of the 5-butynyltriazoles 3 via a Schlenk
complex is depicted in Scheme 2.
In conclusion, we have developed an unprecedented, convenient strategy for the
synthesis of novel, structurally diverse, biologically important bis-1H-1,2,3-triazoles
employing a domino reaction followed by the copper-catalyzed ꢀclick chemistryꢁ
protocol.
A. H. B. and B. S. A. thank the CSIR/UGC, New Delhi, for the award of fellowships.

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Table. Bis-triazoles Prepared by ꢀDomino-Clickꢁ Reaction
Entry Triazole 3
Azide 4
Bis-triazole 5a)
Yield [%]
92
1
2
3
4
91b)
89
91
5
6
88
92

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Table (cont.)
Entry
7
Triazole 3
Azide 4
Bis-triazole 5a)
Yield [%]
90
8
9
90
91
10
11
93
92
12
13
89
90c)

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Helvetica Chimica Acta – Vol. 90 (2007)
Table (cont.)
Entry
Triazole 3
Azide 4
Bis-triazole 5a)
Yield [%]
90
14
15
89
a) All compounds are syrupy liquids/semi-solids unless otherwise mentioned. b) Amorphous white solid, m.p.
195 – 1978. c) Amorphous brown solid, m.p. 175 – 1778.
Scheme 2. Plausible Mechanism for the Formation of 5-Butynyltriazoles 3
Experimental Part
1
General. IR Spectra: Bruker Vector 22 apparatus; in cmÀ1 (%T). H-NMR Spectra: Bruker DPX
apparatus; at 200 (1H) and 50 MHz (13C); chemical shifts d in ppm rel. to Me4Si, coupling constants J in
Hz. ESI-MS: ESI-esquire 3000 Bruker Daltonics apparatus; in m/z. Elemental analyses: Yamaco-CHN
CORDER-MT-3 analyzer; in %.
General Procedure. To a suspension of Mg turnings (1.6 g, 0.66 mol, 10 equiv.) in specially dried THF
with HgCl2 (5 mg, 1wt.-% of propargyl bromide) was added propargyl bromide ( ¼ 3-bromoprop-1-yne;
3.05 ml of an 80 wt.-% soln. in toluene, 4 mmol, 5 equiv.) in small portions while stirring the mixture at r.t.
(note: a small grain of HgCl2 is generally required to promote formation of the reagent). The mixture was

Helvetica Chimica Acta – Vol. 90 (2007)
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stirred at r.t. for 2 h to give a cloudy light green soln. The allenylmagnesium bromide (¼ bromo(propa-
1,2-dien-1-yl)magnesium) generated as above was cooled to 0 – 58 and added dropwise to a soln. of 3-
methylphenyl azide (¼1-azido-3-methylbenzene; 1 g, 0.007 mol) maintaining the temp. between 0 – 58.
The mixture was allowed to attain r.t., and stirring was continued at r.t. for 30 min, followed by quenching
with aq. NH4Cl soln. (10 ml) and diluting with AcOEt (50 ml). The aq. layer was extracted with AcOEt
(2 ꢀ 20 ml), the combined org. layer dried (Na2SO4) and concentrated, and the crude product subjected
to chromatography (silica gel (60 – 120 mesh), hexane/AcOEt gradient): pure 5-(but-3-yn-1-yl)-1-(3-
methylphenyl)-1H-1,2,3-triazole 3 (Entry 13 in Table) as a colorless liquid.
The 5-butynyl-1-(3-methylphenyl) triazole 3 (10 mmol) was stirred in tBuOH/H2O 1:1(10 ml), then
CuSO4 (12 mmol) and sodium ascorbate (50 mmol) were added. After 15 min, 3-methylphenyl azide
(10 mmol) was added, and the mixture, was stirred for 8 h. The mixture was diluted with AcOEt, the aq.
layer extracted with AcOEt (2 ꢀ 20 ml), the combined org. layer dried (anh. Na2SO4), and the solvent
evaporated: crude 5. Precipitation from hexane/AcOEt afforded pure bis-triazole 5 (90%; Entry 13 in
Table) as an amorphous brown solid.
Similarly, other triazoles 3 and bis-triazoles 5 were prepared (see Table): anal. data of a
representative product of type 3 and 5 are given below.
5-(But-3-yn-1-yl)-1-(3-methylphenyl)-1H-1,2,3-triazole (Table, Entry 13): Syrupy brown liquid. IR
(KBr): 3292 (2), 2923 (10), 2853 (43), 2361, 2337 (52), 2118, 1738, 1611 (35), 1592 (30), 1542, 1493, 1384,
1
1257, 1157, 1020 (2), 980, 877, 849, 790, 694 (53), 646. H-NMR (CDCl3): 2.05 (t, J ¼ 2.6, 1H); 2.44 ( s,
3 H); 2.50 (2 H); 2.91( t, J ¼ 7.2, 2 H); 7.20 – 7.43 (m, 4 H); 7.72 (s, 1 H). 13C-NMR (500 MHz, CDCl3):
16.8; 20.3; 22.7; 69.6; 84.7; 121.3; 126.1; 128.3; 129.5; 131.6; 134.8; 136.6. ESI-MS: 233.9 ([M þ Na]þ),
211.9 (78, [M þ 1]þ). Anal. calc. for C13H13N3 (211.27): C 73.91, H 6.20, N 19.89; found: C 74.09, H 6.10, N
20.06.
1-(3-Methylphenyl)-4-{2-[1-(3-methylphenyl)-1H-1,2,3-triazol-5-yl]ethyl}-1H-1,2,3-triazole (Table,
Entry 13). Amorphous brown solid. M.p. 1758. IR (KBr): 3429 (23), 3138 (5), 2922 (50), 2860, 1612
(26), 1593 (29), 1549, 1494 (2), 1383, 1234 (30), 1165 (30), 1089, 1047 (5), 1017, 980, 873, 849, 786 (15),
690 (38), 618. 1H-NMR (CDCl3): 2.33 (s, 3 H); 2.43 (s, 3 H); 3.05 (t, J ¼ 6.2, 2 H); 3.20 (t, J ¼ 6.2, 2 H);
7.25 – 7.59 (m, 8 H); 7.73 (s, 1H); 8.36 ( s, 1 H). 13C-NMR (500 MHz, CDCl3): 19.8; 19.9; 22.9; 23.9; 117.0;
120.4; 122.2; 125.7; 129.2; 129.9; 130.4; 132.1; 135.9; 136.9; 137.8; 140.0; 146.3. ESI-MS: 367 (100, [M þ
Na]þ), 345 (43, [M þ 1]þ). Anal. calc. for C20H20N6 (344.42): C 69.75, H 5.85, N 24.40; found: C 69.80, H
5.82, N 24.51.
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Received July 18, 2007