ZrCl4-mediated synthesis of 1,2,3-triazoles from vinyl nitrates and their biological evaluation

Article abstract of DOI:10.1080/00397911.2016.1270324

A ZrCl₄-mediated simple method for the conversion of vinyl nitrates to 1,2,3-triazoles in excellent yields is developed. The obtained new triazoles were evaluated for their antimicrobial activity.

Full text of DOI:10.1080/00397911.2016.1270324

ZrCl4 Mediated synthesis of 1,2,3-triazoles from vinyl nitrates and their biological
evaluation
Gattu Sridhar1, Mudavath Somnath1, Gangavaram V. M. Sharma1, Thodupunuri
Prashanth1
1Organic and Biomolecular Chemistry Division,CSIR-Indian Institute of Chemical
Technology, Hyderabad, India
Address correspondence to Gattu Sridhar. E-mail: sridhar1org@yahoo.com
Abstract
A ZrCl4 mediated simple method for the conversion of vinyl nitrates to 1,2,3-triazoles in
excellent yields is developed. The obtained new triazoles were evaluated for their anti-
microbial activity.
GRAPHICAL ABSTRACT
KEYWORDS: Zirconium(IV)chloride, CH3NO2, vinyl nitrates, 1,2,3-triazoles.
INTRODUCTION
1,2,3-Triazoles are very important class of compounds belonging to heterocycles.1 These
compounds found wide use in diverse fields of applications such as pharmaceuticals,
agrochemicals and materials.2 The triazole systems have been implicated in a wide
spectrum of biological activities,3 such as antibacterial,4 herbicidal, fungicidal,
1

antiallergic, anti-HIV 5 properties and are expected to become medicines to treat cancers
and some other serious diseases.6
1,2,3-Triazole moieties are attractive connecting units because they are stable to
metabolic degradation and capable of hydrogen bonding, which can be favourable in the
binding of bio-molecular targets and can improve the solubility. The 1,2,3-triazole moiety
does not occur in nature, although the synthetic molecules that contain 1,2,3-triazole units
show diverse biological activities.
Though for the synthesis of triazoles, the copper(I)-catalyzed azide–alkyne cycloaddition
reaction has been the method of choice, several new methodologies were developed and
have been demonstrated to be powerful alternatives. The strain-promoted azide–alkyne
and azide-alkene cycloaddition reaction is one such development under Cu free
conditions. Organocatalytic [3+2]-cycloaddition reactions7 have shown immense
potential to become the next generation of preferred method for the metal-free synthesis
of triazole. The synthesis of 1,2,3-triazoles, there is still significant room for
improvement, both in terms of substrate scope as well as reaction conditions.
Recently sheng et al, An efficient, one-pot, three-step, synthesis of 1,2,3-triazoles, has
been developed via four-component reaction of phenylselenenyl bromide, cyclohexene,
sodium azide and terminal alkynes catalyzed by copper iodide in a mixture of DMF/THF
(1:1) at room temperature under mild conditions.
2

In continuation of our interest on the catalytic applications of ZrCl48,9 as a Lewis acid for
various organic transformations, herein we report the ZrCl4 mediated synthesis of 1,2,3-
triazoles from vinyl nitrates, and their biological evaluation.
Based on our earlier studies on the conversion of benzylic carbinols to azides in the
presence of ZrCl4, carbinol A was subjected to reaction with ZrCl4 to give B (Scheme 1).
However, instead reaction of A with ZrCl4 gave vinyl nitrate B. A method for the
conversion of C to D with PTSA in DMF at 60 ºC was reported,10 while our work was in
progress for the conversion of C to D with ZrCl4.
RESULTS AND DISCUSSION
Aldehyde 1 on reaction with CH3NO2 in the presence of ZrCl4 (5 mol%) for 3 h gave
vinyl nitrate 1a, which on further reaction with NaN3 in the presence of ZrCl4 (5 mol%)
for 18 h at room temperature gave 1,2,3-triazole 14 in 91% of yield (Scheme 2). To
standardization of catalyst reaction of 1a in CH3NO2 with different mol% of ZrCl4 (5, 10,
15) revealed that 5 mol% is the optimum quantity.
The two step protocol was extended to aldehydes 2-13 under the above reaction
conditions to give the corresponding 1,2,3-triazoles 15 (90%), 16 (94%), 17 (94%), 18
(96%), 19 (92%), 20 (93%), 21 (91%), 22 (93%), 23 (95%), 24 (96%), 25 (95%) and 26
(96%) respectively (Scheme 2). The reaction was found to be very general and
irrespective of different functional groups, it was facile to afford the triazoles in high
yields.
3

Encouraged by the above synthetic transformation by the use of ZrCl4 (5 mol%), the
study was then extended to sugar derived aldehydes. Accordingly, reaction of aldehydes
27, 28, and 29 (Schemes 3) with CH3NO2 in the presence of ZrCl4 at room temperature
furnished the vinyl nitrates 27a-29a. Further, treatment of 27a-29a with ZrCl4 (5 mol%)
and NaN3 afforded the corresponding 1,2,3-triazoles 30 (93%), 31 (93%) and 32 (95%)
respectively (Scheme 3). Likewise 28a on reaction with PMBN3 in CH3NO2 at room
temperature gave 31a in 91% of yield.
Similarly, ZrCl4 catalyzed reactions of several vinyl nitrates with benzyl and PMB azides
for 24 h in CH3NO2 at room temperature furnished 1,2,3-triazoles 33-40 respectively
(Scheme 4).
Antimicrobial Activity Of Triazoles
As the triazoles are known to be powerful antimicrobial agents,11 the synthetic triazoles
were evaluated for their antibacterial behavior (Table 1) against Gram-negative (P.
aeruginosa, S. typhi) and Gram-positive (B. subtilis, S. aureus) microbial strains. All the
synthetic triazoles showed intreasting antibacterial activity against the tested cultures.
Maximum activity was indicated for triazole 40 against P. aeruginosa (30 mm), and B.
subtilis (29 mm), whereas, minimum activity observed was for triazole 20. Further
observations revealed that the triazoles, 21, 35, 37, and 39 showing good intensity of
antibacterial activity compared with others.
4

In summary a ZrCl4 mediated conversion of vinyl nitrates to triazole has been developed.
The present method is simple, efficient and high yielding. The new triazole have shown
moderate to weak anti microbial activity.
Experimental Section
4-(3-(Benzyloxy)-4-Methoxyphenyl)-1H-1,2,3-Triazole (14)
To a stirred solution of 1a (0.2 g, 0.7 mmol) in nitromethane (2 mL), NaN3 (0.05 g, 0.84
mmol) and ZrCl4 (0.06 g, 0.28 mmol) was stirred at room temperature for 18 h. The
reaction mixture was treated with H2O (10 mL) and extracted with EtOAc (3×10 mL).
The organic layers were dried (Na2SO4), evaporated under reduced pressure and purified
the residue by column chromatography (60-120 mesh silica gel, 14% ethyl acetate in pet.
ether) to furnish 14 (0.18 g, 91%) as a white solid. m.p. 137-139 °C; 1H NMR (300 MHz,
CDCl3+DMSO): δ 7.80 (s, 1H, Olefinic), 7.52-7.44 (m, 3H, ArH-Bn), 7.42- 7.30 ( m, 4H,
ArH-Bn), 6.96 (d, 2H, J = 8.4 Hz, ArH-Bn), 5.20 (s, 2H, benzylic), 3.90 (s, 3H, -OCH3);
13C NMR (CDCl3 + DMSO, 75 MHz): 148.6, 147.2, 135.8, 127.3, 126.8, 126.5, 117.9,
111.1, 110.6, 69.7, 54.8; IR (neat): 3273, 3137, 3064, 3008, 2924, 2652, 1611, 1588,
1506, 1458, 1422, 1379, 1313, 1252, 1176, 1140, 1079, 992, 770, 667 cm-1; HRMS
(ESI): m/z calculated for C16H15O2N3 Na [M+Na]+ 304.1165, found 304.1170.
1-Benzyl-4-(2,4-Dimethoxyphenyl)-1H-1,2,3-Triazole (33)
To a stirred solution of 3a (0.2 g, 0.9 mmol) in nitromethane (3 mL) was treated with
benzyl azide (0.15 g, 1.14 mmol), ZrCl4 (0.08 g, 0.38 mmol) and at room temperature in
air for 24 h. The reaction mixture was treated with H2O (10 mL) and extracted with
5

EtOAc (3×10 mL). The organic layer was dried (Na2SO4), evaporated under reduced
pressure and purified the residue by column chromatography (60-120 mesh silica gel,
20% ethyl acetate in pet. ether) to furnish 33 (0.26 g, 92%) as a white solid. m.p. 125-127
°C; 1H NMR (300 MHz, CDCl3+DMSO): δ 7.61 (s, 1H, Olefinic), 7.25-7.19 (m, 3H,
Aromatic), 7.05-6.94 (m, 3H, Aromatic), 6.54-6.47 (m, 2H, Aromatic), 5.40 (s, 2H,
benzylic), 3.84 (s, 3H, -OCH3), 3.67 (s, 3H, -OCH3); 13C NMR (75 MHz,
CDCl3+DMSO): 161.3, 156.8, 134.6, 133.8, 132.6, 130.9, 127.3, 126.6, 126.3, 106.6,
104.0, 97.6, 54.4, 50.7; IR (neat): 3448, 3005, 2938, 2840, 1616, 1579, 1492, 1458, 1302,
1264, 1240, 1209, 1161, 1121, 1074, 1028, 973, 933, 832, 717, 638 cm-1; HRMS (ESI):
m/z calculated for C17H17N3O2Na [M+Na]+ 318.1320, found 318.1326.
1-(4-Methoxybenzyl)-4-(2,3,4-Trimethoxyphenyl)-1H-1,2,3-Triazole (37)
To a stirred solution of 4a (0.2 g, 0.83 mmol) in CH3NO2 (3 mL) was treated with p-
methoxybenzyl azide (0.16 g, 1.0 mmol) and ZrCl4 (0.07 g, 0.33 mmol) and at room
temperature in air for 24 h. The reaction mixture was treated with H2O (10 mL) and
extracted with EtOAc (3×10 mL). The organic layers were dried (Na2SO4), evaporated
under reduced pressure and purified the residue by column chromatography (60-120
mesh silica gel, 21% ethyl acetate in pet. ether) to furnish 37 (0.279 g, 94%) as a white
solid. m.p. 126-128 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ 7.62 (s, 1H, Olefinic),
6.93 (d, 2H, J = 8.4 Hz, Aromatic), 6.82-6.78 (m, 1H, Aromatic), 6.76-6.70 (m, 3H,
Aromatic), 5.42 (s, 2H, benzylic), 3.91 (s, 6H, 2 x -CH3), 3.73 (s, 3H, -OCH3), 3.58 (s,
3H, -OCH3); 13C NMR (75 MHz, CDCl3+DMSO): 158.1, 154.3, 141.3, 133.1, 132.7,
128.0, 126.4, 124.4, 112.8, 112.3, 106.6, 59.9, 55.0, 54.1, 50.5; IR (neat): 3448, 2935,
6

2841, 1610, 1555, 1513, 1485, 1464, 1324, 1292, 1247, 1177, 1099, 1078, 1008, 979,
917, 768, 694 cm-1; HRMS (ESI): m/z calculated for C19H21N3O4Na [M+Na]+ 378.1531,
found 378.1537.
SUPPORTING INFORMATION
Full experimental details, spectral data of the products, 1H NMR and 13C NMR of all the
new compounds can be found via the Supplementary Content section of this article’s
Web page.
CONCLUSION
In conclusion, an efficient method for the conversion of vinyl nitrates to 1,2,3-triazoles
catalyzed by ZrCl4 has been developed in good yields. The derived triazoles were
evaluated for their antimicrobial activity against Gram-positive and Gram-negative
bacteria.
ACKNOWLEDGEMENTS
The authors are thankful to CSIR, New Delhi, for financial support (CSC-0108; BSC-
0116). GSR is thankful to CSIR, New Delhi, India, for the award of research fellowship.
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Table 1. Antibactirial activity of triazole derivatives
Entry
1
Triazoles B.subtilis P.aeruginosa S.typhi S.aureus
19.5
17
18
16
18.5
14
15
16
17
18
19
20
21
22
23
24
25
26
30
31
32
33
34
35
37
38
2
16
15
11.5
3
12
-
-
-
4
14.5
12.5
18.5
10.5
24.5
11
13.5
12.5
20.5
12.5
23.5
11.5
12.5
19.5
14.5
14.5
11.5
12.5
11
14.5
11
-
5
-
6
21
-
7
11.5
19
-
8
18.5
9
11.5
11
-
10
11
12
13
14
15
16
17
18
19
20
21
10
-
12
12.5
19.5
12
-
14.5
14.5
15.5
12.5
13.5
13.5
18.5
20
-
11
-
11
12.5
-
-
-
12.5
20
13
12
14.5
14.5
11.5
-
12.5
12.5
11.5
14.5
14
24.5
15.5
17.5
14.5
10

22
21.5
29
24.5
30
22.5
26.5
13
22.5
26.5
11.5
20.5
39
23
40
24
12.5
21
11
31a
Standard
25.5
21
11

Scheme 1.
12

Scheme 2.
13

Scheme 3.
14

Scheme 4.
15