A facile access for the synthesis of 1-hetero(aryl)-1,2,3-triazoles linked to equol under mild conditions

Article abstract of DOI:10.1080/00397911.2020.1792932

We herein report a convenient methodology for the synthesis of 1-hetero(aryl)-1,2,3-triazoles linked with equol by utilizing copper-catalyzed azide-alkyne cycloaddition reaction under exceptionally mild conditions. The salient features of this developed p

Full text of DOI:10.1080/00397911.2020.1792932

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A facile access for the synthesis of 1-
hetero(aryl)-1,2,3-triazoles linked to equol under
mild conditions
Muthipeedika Nibin Joy , Nikolai Beliaev , Tetyana V. Beryozkina & Vasiliy A.
Bakulev
To cite this article: Muthipeedika Nibin Joy , Nikolai Beliaev , Tetyana V. Beryozkina & Vasiliy A.
Bakulev (2020): A facile access for the synthesis of 1-hetero(aryl)-1,2,3-triazoles linked to equol
under mild conditions, Synthetic Communications, DOI: 10.1080/00397911.2020.1792932
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https://doi.org/10.1080/00397911.2020.1792932
A facile access for the synthesis of 1-hetero(aryl)-1,2,3-
triazoles linked to equol under mild conditions
Muthipeedika Nibin Joya, Nikolai Beliaevb, Tetyana V. Beryozkinab, and
Vasiliy A. Bakulevb
aInnovation Center for Chemical and Pharmaceutical Technologies, Institute of Chemical Technology,
b
Ural Federal University, Yekaterinburg, Russia; TOS Department, Ural Federal University,
Yekaterinburg, Russia
ABSTRACT
ARTICLE HISTORY
Received 19 May 2020
We herein report a convenient methodology for the synthesis of 1-
hetero(aryl)-1,2,3-triazoles linked with equol by utilizing copper-cata-
lyzed azide-alkyne cycloaddition reaction under exceptionally mild
conditions. The salient features of this developed protocol include:
easy isolation process, good to excellent yield of the products and
appendage diversity of heteroaryl triazoles.
KEYWORDS
Copper; cycloaddition;
equol; 1,2,3-triazole
GRAPHICAL ABSTRACT
Introduction
Equol is an isoflavonoid that belongs to the class of polyphenols which exist in two
enantiomeric forms. They exhibit a wide range of biological activities like anti-
androgenic, antioxidant and anti-inflammatory potencies.[1] Equol significantly reduces
bone loss and is reported to improve skin health and regeneration because of its antiox-
idative, phytoestrogenic and epigenetic characteristics.[2] In living organisms, equol is
metabolized from the isoflavone daidzein by intestinal bacteria. Equol is also synthesized
in the laboratories from the last 50 years; initially in racemic form and recently as separ-
ate enantiomers.[3] Highly functionalized molecules comprising of linearly connected
heterocyclic rings have received considerable interest in recent years owing to their
diverse pharmacological activity[4] and their applications in organic synthesis as well as
material chemistry.[5] Among these, 1,2,3-triazole derivatives are highly important
because of their varied biological and chemical properties.
CONTACT Muthipeedika Nibin Joy
mnibinjoy@gmail.com
Innovation Center for Chemical and Pharmaceutical
Technologies, Institute of Chemical Technology, Ural Federal University named after the first President of Russia B N
Yeltsin, Mira 19, Yekaterinburg 620002, Russia; Vasiliy A. Bakulev
Federal University, Yekaterinburg 620002, Russia.
v.a.bakulev@urfu.ru
TOS Department, Ural
Supplemental data for this article can be accessed on publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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N. J. MUTHIPEEDIKA ET AL.
Scheme 1. An overview of reports on CuAAC.
The discovery of copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction by
the groups of Meldal and Sharpless paved the way for the synthesis of a wide variety of
monocyclic, spirocyclic and fused 1,2,3-triazoles.[5g,6] Moreover, several 1,2,3-triazole
derivatives linearly connected to other heterocycles were found to exhibit potential anti-
viral,[4c,5h] anticancer and antibacterial properties.[4d,g] In the design and development
of new drugs, the molecular hybridization strategy involving the combination of two or
more pharmacophores in a single entity is presumed to generate new compounds with
interesting biological profiles.[4d,7] Although the synthesis of 1,2,3-triazoles by CuAAC
is a well-explored area in synthetic chemistry for the past two decades, the reaction of
electron-deficient heteroaryl azides has always been a challenging problem.[8] Moreover,
the synthesis of hybrids of 1-heteroaryl-1,2,3-triazoles and equol is surprisingly undone
whereas the preparation of 1-aryl-1,2,3-triazoles linked with daidzein is limited to only
one example (Scheme 1).[9] These observations enlightened us about the challenges
associated with their synthesis and hence we directed our attention towards developing
a facile and convenient one-pot approach for the synthesis of hybrids of 1-heteroaryl-
1,2,3-triazoles and equol linearly connected via flexible oxymethylene linker.
Results and discussion
As depicted in Scheme 2, we started our synthetic route by the selective methylation of
daidzein 1. The intermediate thus obtained was then reduced to equol intermediate 3
by hydrogenation reaction. This methylated equol intermediate 3 was then treated with
propargyl bromide and various azides sequentially in one-pot for obtaining a series of
1-hetero(aryl)-1,2,3-triazoles linked with equol.

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3
Scheme 2. Synthesis of methylated equol intermediate 3.
As a model reaction, we took the equol intermediate 3 and 5-azido-1-methyl-4-nitro-
1H-imidazole 4a for performing the synthesis of 1,2,3-triazoles. The initial optimization
studies were focused on synthesizing the desired compounds in two steps: by initial syn-
thesis of O-propargylated intermediate and then treating that alkyne with hetero-
aromatic azides (see supporting info). Nevertheless, we were grateful to obtain the
desired products in a one-pot methodology after careful screening of the reaction
parameters (see supporting info for more details). The reaction proceeded smoothly at
room temperature in the presence of CuI as a catalyst, potassium carbonate as the base
and acetone as solvent (Table 1, entry 4). When potassium carbonate was replaced with
organic bases, the yield of the required product decreased significantly (Table 1, entries
6 and 7). The use of CuBr instead of CuI also diminished the yield of the expected
1,2,3-triazole product (Table 1, entry 8). Among the solvents screened, acetone was
found to be essential for better conversions (Table 1, entries 9 and 10). The detailed
optimization studies are described in the Supporting Information and the optimum
reaction conditions were as illustrated in entry 4 of Table 1. Gratifyingly, this developed
methodology eased us to achieve the otherwise two-step synthesis of required products
in one step in excellent yield.
After establishing a facile protocol for the one-pot synthesis of equol linked with
1,2,3-triazole, we directed our attention towards evaluating the substrate scope of the
developed protocol. Accordingly, we treated the methylated equol intermediate 3 with
propargyl bromide and different heteroaryl azides 4a–l in our optimized reaction condi-
tions. To our delight, we obtained the desired 1-heteroaryl-1,2,3-triazoles 5a–l in good
to excellent yields in all these reactions (Scheme 3). The various heterocyclic azides of
uracil, thiophene, isoxazole, pyrazole, and imidazole reacted well efficiently to procure
the desired products in excellent yields. The azides of benzothiazole and thiazole ren-
dered the desired product in good yield only when stoichiometric amount of CuI was
used which could be rationalized by the existence of those azides in its tetrazole
form.[10] Moreover, our developed methodology also procured the expected products
(5k and 5l) in satisfactory yield when the antiretroviral drug, azidothymidine
(Zidovudine) and its methyl derivative were employed for the CuAAc reaction. The util-
ization of hitherto unreported aromatic azides 4m–n also procured the corresponding
products 5m–n in good yield.

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N. J. MUTHIPEEDIKA ET AL.
Table 1. Optimization of the reaction conditions.a
Br
K2CO3
(equiv.)
Azide
(equiv.)
Yieldb
5a (%)
Entry
(equiv.)
1
2
3
4
5
1
1
1
2
3
3
1
1
1
1
50
60
80
90
75
1.5
1.5
1.5
1.5
1.5
Deviation from the above standard conditions (entry 4)
TEA instead of K2CO3 (35% of 3 recovered)
DIPEA instead of K2CO3 (30% of 3 recovered)
CuBr instead of CuI
6
7
8
9
50
60
40
25
NR
DMF instead of acetone (60% of 3 recovered)
H2O instead of acetone (90% of 3 recovered)
10
aReaction conditions: 3 (1.0 mmol), propargyl bromide (1.5 mmol), base (3.0 mmol), solvent (3 mL), rt, 10 h. 4a
(1.0 mmol), catalyst (0.1 mmol), rt, 3 h. bIsolated yield.
The newly synthesized compounds 5a–n was recrystallized from EtOH without any
additional purification techniques and the structure of all the final compounds was
characterized by the NMR and mass spectral analysis. Moreover, the structure of 5h[11]
was confirmed by single crystal XRD analysis (Figure 1).
In order to check the feasibility of the developed methodology at higher dimensions,
a scale-up reaction was carried out at the later stage. Gratifyingly, the gram-scale reac-
tion procured the expected product 5a in satisfactory yield (85% isolated yield) as the
same reaction in small-scale furnished the desired product in 90% yield (Scheme 3).
A
representative experimental procedure for the synthesis of 4-((4-(7-
Methoxychroman-3-yl)phenoxy)methyl)-1-(1-methyl-4-nitro-1H-imidazol-5-yl)-1H-
1,2,3-triazole (5a) is detailed here. To the solution of 4-(7-methoxychroman-3-yl)phenol
3 (0.256 g, 1 mmol, 1 equiv.) in acetone (3 mL), K2CO3 (0.415 g, 3 mmol, 3 equiv.) and
propargyl bromide (0.178 g, 1.5 mmol, 1.5 equiv.) were added in inert atmosphere and
the reaction mixture was stirred at room temperature for 10 h. After the completion of
reaction monitored by TLC, azide 4a (1 mmol, 1 equiv.) and CuI (0.019 g, 10 mol %, 0.1
equiv.) were added to the same reaction vessel and the mixture was stirred at room
temperature for another 3–5 h. After the completion of reaction monitored by TLC, the
reaction mixture was filtered through celite and distilled under reduced pressure to
obtain the crude product. The crude product was further recrystallized from ethanol to
obtain the titled compound 5a as light yellow solid in 90% yield. Mp 201–203 ꢀC. IR
(KBr): 3849, 3122, 2919, 1611, 1580, 1527, 1504, 1461, 1433, 1378, 1355, 1319, 1288,
1
1262, 1232, 1196, 1156, 1111, 1017, 868, 827, 775, 648, 539 cmꢁ1. H NMR (400 MHz,
DMSO-d6): d ¼ 2.88–2.96 (m, 2H), 3.12–3.15 (m, 1H), 3.55 (s, 3H), 3.70 (s, 3H), 4.01

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Figure 1. Compound 5h according to XRD data in the thermal ellipsoids of 50% probability level.
Scheme 3. Substrate scope of the developed methodology.a aReaction conditions: (1) 3 (1.0 mmol),
propargyl bromide (1.5 mmol), K2CO3 (3.0 mmol), acetone (3 mL), rt, 10 h; 2) 4a–n (1.0 mmol), CuI
b
c
d
(0.1 mmol), rt, 3 h. Isolated yield. The gram-scale reaction yield. 1.0 mmol of CuI used.

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N. J. MUTHIPEEDIKA ET AL.
(t, J ¼ 10.4 Hz, 1H), 4.22 (d, J ¼ 10.4 Hz, 1H), 5.29 (s, 2H), 6.37 (d, J ¼ 2.4 Hz, 1H), 6.46
(dd, J ¼ 2.4, 8.4 Hz, 1H), 7.01 (d, J ¼ 8.4 Hz, 1H), 7.06 (d, J ¼ 8.4 Hz, 2H), 7.29 (d,
J ¼ 8.8 Hz, 2H), 8.14 (s, 1H), 8.79 (s, 1H). 13C NMR (100 MHz, DMSO-d6): d ¼ 31.1,
32.3, 36.9, 55.0, 60.8, 70.1, 101.1, 106.8, 114.1, 114.9, 123.4, 128.4, 128.5, 130.2, 134.0,
136.1, 139.0, 143.2, 154.6, 156.8, 158.6. MS (EI): m/z (%) ¼ 462 (1) [M]þ, 137 (100).
Anal. Calcd for C23H22N6O5: C, 59.73; H, 4.80; N, 18.17. Found: C, 59.39; H, 4.45;
N, 17.88.
Conclusion
A facile and convenient methodology has been developed for the sequential one-pot
synthesis of 1-hetero(aryl)-1,2,3-triazoles linked with equol under mild conditions. The
reaction was found to be tolerant with a wide variety of heteroaryl azides which point
toward its broad scope and diversity. The protocol described here can be extended for
the synthesis of diverse triazole hybrids linked to other complex molecules in future.
The detailed experimental procedure and characterization data including spectra are
available in the Supporting information uploaded along with the manuscript.
Funding
The authors are thankful to Russian Science Foundation [Grant # 18-13-00161].
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