3-Mercapto-1,2,4-triazole Functionalized Fe3O4 Based Cu Nanoparticles: A Capable Catalyst for the Synthesis of Diverse Tetrazoles from Amino Acids

Full text of DOI:10.1080/00304948.2020.1716624

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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3-Mercapto-1,2,4-triazole Functionalized Fe3O4
Based Cu Nanoparticles: A Capable Catalyst for the
Synthesis of Diverse Tetrazoles from Amino Acids
Vahideh Khorramabadi, Davood Habibi & Somayyeh Heydari
To cite this article: Vahideh Khorramabadi, Davood Habibi & Somayyeh Heydari (2020): 3-
Mercapto-1,2,4-triazole Functionalized Fe3O4 Based Cu Nanoparticles: A Capable Catalyst for
the Synthesis of Diverse Tetrazoles from Amino Acids, Organic Preparations and Procedures
International, DOI: 10.1080/00304948.2020.1716624
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1716624
EXPERIMENTAL PAPER
3-Mercapto-1,2,4-triazole Functionalized Fe3O4 Based Cu
Nanoparticles: A Capable Catalyst for the Synthesis of
Diverse Tetrazoles from Amino Acids
Vahideh Khorramabadia, Davood Habibia, and Somayyeh Heydaria,b
aDepartment of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran;
bDepartment of Research and Development, Faran Shimi Pharmaceutical Company, Tuyserkan, Iran
ARTICLE HISTORY Received 6 May 2019; Accepted 28 September 2019
Tetrazoles are an important class of heterocycles combining high nitrogen content with
significant biological properties. Among these are activities as sedatives,1 antibacterials,2
anticancer drugs,3 antidiabetic medications,4 antifungals,5 anti-inflammatories,6 general
antimicrobials,7 antitumor compounds,8 antivirals,9 carboxylic acid isosteres,10 diu-
retics11 and herbicides.12
In continuation of our previous work on the application of magnetic nanoparticle
metal complexes as heterogeneous catalysts for the synthesis of heterocyclic com-
pounds,13 we would now like to report the preparation of the novel title Cu nano-cata-
lyst. Our motivation was to promote a new efficient nano-catalyst for greener methods
and potentially lower costs for the synthesis of heterocycles. The catalyst preparation
occurred via a multistep process including: the synthesis of the Fe3O4 magnetic nano-
particles, coating the latter with tetraethyl orthosilicate (TEOS) (Fe3O4/SiO2), functional-
ization of Fe3O4/SiO2 with 3-chloropropyltrimethoxysilane (CPTMS) and 3-mercapto-
1,2,4-triazole (MT) ligands (Fe3O4/SiO2/CPTMS/MT), and further complexation with
CuCl2 (Fe3O4/SiO2/CPTMS/MT/Cu). In a demonstration of its utility for diversity in
synthesis, the new Cu magnetic nano-catalyst was subsequently used for the synthesis of
a variety of useful tetrazoles from the reaction of amino acids with sodium azide and
triethyl orthoformate (TEOF) in H2O at 40 ꢀC (Scheme 1). To the best of our know-
ledge, this is the first such application.
The catalyst activity was optimized in a model reaction. This was the synthesis of
3-(1H-indol-3-yl)-2-(1H-tetrazol-1-yl)propanoic acid (2c) from the reaction of trypto-
phan with sodium azide and TEOF. The model was run under different conditions of
temperature, amount of the catalyst and solvents. The best result was obtained with
10 mmole of amino acid, 10 mmole of sodium azide, 30 mmole of TEOF and 20 mg of
the Cu nano-particle catalyst in H2O at 407ꢀC (Tables 1-3).
Applying the optimized results from the model, a number of tetrazoles were prepared
with good to excellent yields (Table 4).
All of the compounds were fully characterized (see Experimental section).
CONTACT Davood Habibi
davood.habibi@gmail.com
Department of Organic Chemistry, Faculty of Chemistry, Bu-
Ali Sina University, Hamedan, Iran
ß 2020 Taylor & Francis Group, LLC

2
V. KHORRAMABADI ET AL.
Scheme 1. Synthesis of the new Cu magnetic nano-catalyst and diverse tetrazoles.
Table 1 Effect of solvent on the synthesis of 2c at 40 ꢀC.
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
H2O
EtOH
MeOH
EtOAc
n-Hexane
Toluene
CHCl3
3
3
3
6
4
7
5
87
83
80
84
79
83
85
Table 2 Effect of temperature on the synthesis of 2c in H2O.
Entry
Temp (˚C)
Time (h)
Yield (%)
1
2
3
4
5
r.t.
40
60
80
1
1
1
1
1
84
89
85
87
85
reflux
Table 3 Effect of amount of the catalyst on the synthesis of 2c in H2O at 40 ꢀC.
Entry
Catalyst (mg)
Time (h)
Yield (%)
1
2
3
4
5
6
No catalyst
5
10
20
30
50
1
1
1
1
1
1
Very low
85
86
88
86
86
The reusability of Fe3O4/SiO2/CPTMS/MT/Cu was investigated with the model reaction
to find the recycling capability of the catalyst. The catalyst was separated by filtration after
the first run, washed with ethanol and dried under vacuum, then reused for the next suc-
cessive runs under the same conditions. We found that the Cu nano-catalyst could be
reused even after five runs; the catalytic activity in the fifth run was almost as same as the
first for the preparation of the model tetrazole (97, 95, 92, 90 and 87%, respectively).
In conclusion, the novel heterogeneous Cu nano-catalyst was successfully prepared in
five stages and used for the synthesis of diverse tetrazoles from the reaction of several

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Table 4 Synthesis of tetrazoles (2a-h).
Entry
1
Amino acid
Product
Time (h)
2
Yield (%)
86
2
1
92
3
4
1
5
94
80
5
6
3
7
93
91
7
1
73
(continued)

4
V. KHORRAMABADI ET AL.
Table 4 Continued.
Entry
8
Amino acid
Product
Time (h)
2
Yield (%)
75
amino acids with sodium azide and TEOF in water at 40 ꢀC. Given its usefulness, it is
our hope that other researchers will take up this catalyst for their syntheses of hetero-
cyclic compounds.
Experimental section
All reagents were purchased from Merck and Aldrich and used without further purifica-
tion. The NMR spectra were recorded in the appropriate deuterated solvents, as noted
1
in the individual procedures. HNMR and 13C NMR spectra were recorded on a Bruker
Avance 300 MHz instrument. FT-IR (KBr) spectra were recorded on a Perkin Elmer 781
spectrophotometer. Melting points were taken in open capillary tubes with a BUCHI
510 melting point apparatus and are uncorrected. Elemental analysis was performed
using a Heraeus CHNO-Rapid analyzer. The inductively coupled plasma (ICP) measure-
ments for the metal content evaluation were performed using a Perkin-Elmer ICP/6500.
TLC was performed on silica gel polygram SIL G/UV 254 plates, using the mixture of
AcOEt/n-hexane (40:60) as the moving phase. The TEM images were recorded on a
Zeiss-EM10C-100 KV transmission electron microscope. The SEM images were recorded
on a Philips XL-30 scanning electron microscope. The X-ray diffraction (XRD) meas-
urements were done by a Bruker D8 Advance powder diffractometer, using Cu Ka
(k ¼ 1.54 A) as the incident radiation. Dispersive X-ray spectroscopy (EDX) was deter-
mined on an Oxford instrument. Thermogravimetric-differential thermal analysis (TG-
DTA) was determined by the Perkin Elmer Pyris Diamond instrument. Magnetic meas-
urements were carried out at room temperature using an Iranian Meghnatis Daghigh
Kavir Co. Vibrating Sample Magnetometer (VSM). TEM, XRD, EDX, TG-DTA and
VSM data are available from the corresponding author upon request.
Preparation of the Cu nano-catalyst
Stage 1: Preparation of the Fe3O4 magnetic nanoparticles (Fe3O4 MNPs). The mixture of
FeCl3ꢁ6H2O (11.44g, 42mmol) and FeCl2ꢁ4H2O (4.3g, 21mmol) was dissolved in water
(100 mL), and the solution stirred for 0.5 h in 80 ꢀC. A solution of 37% ammonia was then
added dropwise with vigorous stirring. A black solid product was obtained when the

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
reaction medium reached pH 10. The mixture was heated for 0.5 h at 70 ꢀC and the black
magnetite solid product filtered, washed with water and dried at 80 ꢀC for 12 h.
Stage 2: Coating of Fe3O4 MNPs with TEOS. Fe3O4. MNPs (0.2 g) were dispersed in
EtOH/H2O (250 mL, V/V ¼ 4:1) with NH3ꢁH2O (3 mL) solution under ultrasonication.
Then, TEOS (2 mL) was slowly added dropwise and the mixture stirred for a further
6 h. Fe3O4/SiO2 was obtained by centrifugation, washed with water and ethanol several
times, and dried in vacuo.
Stage 3: Functionalization of Fe3O4/SiO2 with the CPTMS ligand. The CPTMS ligand
(1.0 mL, 5 mmol) was dissolved in dry toluene (100 mL) and Fe3O4/SiO2 (1.0 g) added
and stirred for 18 h at 60 ꢀC. Then, the obtained product (Fe3O4/SiO2/CPTMS) was sep-
arated with a strong magnet, washed with toluene and dried in vacuo.
Stage 4: Further functionalization with the MT ligand. The MT ligand (0.5 g, 5 mmol)
and K2CO3 (0.69 g, 5 mmol) in toluene (60 mL) were added to Fe3O4/SiO2/CPTMS (0.1 g)
and refluxed for 12 h. Then, the obtained product (Fe3O4/SiO2/CPTMS/MT) was separated
with a strong magnet, washed repeatedly with ethanol and water and dried in vacuo.
Stage 5: Complexation of Fe3O4/SiO2/CPTMS/MT with CuCl2. Fe3O4/SiO2/CPTMS/
MT (0.1 g) was added to dispersed CuCl2 (0.85 g, 5 mmol) in ethanol (20 mL) and
stirred vigorously for 8 h at 80 ꢀC. Then, the resulting Cu nano-catalyst (Fe3O4/SiO2/
CPTMS/MT/Cu) was separated with a strong magnet, washed with ethanol and air-
dried (Scheme 1).
General procedure for the synthesis of tetrazoles
Amino acid (10 mmol), sodium azide (0.65 g, 10 mmol) and the Cu nano catalyst
(20 mg) were added to a solution of TEOF (4.4 g, 5 mL, 30 mmol) in H2O (5 mL). The
solution was stirred and the mixture heated at 40 ꢀC for 1-7 h depending on the sub-
strate. Completion of the reaction was monitored by TLC. Then, H2O (20 mL) was
added, the Cu catalyst filtered, the filtrate concentrated and the solvent removed in
vacuo. The obtained tetrazoles were recrystallized from ethanol and were fully character-
ized, including satisfactory elemental analyses.
2-Phenyl-2-(1H-tetrazol-1-yl)acetic acid (2a)
White crystals, mp 158-160 ꢀC; IR (KBr) 3127 (CHtetrazole), 2970 (CHstretch), 1752
1
(C ¼ O) (cmꢂ1). H NMR (300 MHz, acetone-d6): d 6.85 (s, 1 H, CH), 7.46-7.55 (m,
5 Haromatic), 9.20 (s, 1 Htetrazole). 13C NMR (75 MHz, acetone-d6): d 63.10 (CH), 127.83
(CHp-aromatic), 127.83 (2 CHm-aromatic), 128.25 (2 CHo-aromatic), 131.63 (Caromatic), 141.93
(CHtetrazole), 166.58 (C ¼ O).
Anal. Calcd for C9H8N4O2: C, 52.94; H, 3.95; N, 27.44. Found: C, 52.71; H, 3.87;
N, 27.34.
3-Phenyl-2-(1H-tetrazol-1-yl)propanoic acid (2b)
White crystals, mp 156-158 ꢀC; IR (KBr): 3443 (COOH), 3130 (CHtetrazole), 1725
1
(C ¼ O) (cmꢂ1). H NMR (300 MHz, acetone-d6): d 3.09 (m, 2 H, CH2), 5.44 (m, 1 H,

6
V. KHORRAMABADI ET AL.
CH), 6.85 (s, 5 Haromatic), 8.95 (s, 1 Htetrazole). 13C NMR (75 MHz, acetone-d6): d 36.31
(CH2), 61.64 (CH), 126.89 (CHp-aromatic), 128.36 (2 CHm-aromatic), 128.70 (2 CHo-aromatic),
135.57 (Caromatic), 144 (CHtetrazole), 168.87 (C ¼ O).
Anal. Calcd for C10H10N4O2: C, 55.04; H, 4.62; N, 25.68. Found: C, 55.06; H, 4.63;
N, 25.57.
3-(1H-indol-3-yl)-2-(1H-tetrazol-yl)propanoic acid (2c)
Yellow crystals, mp 82-85 ꢀC; IR (KBr) 3387 (COOH & NH), 3129 (CHtetrazole), 1725
1
(C ¼ O) (cmꢂ1). H NMR (300 MHz, acetone-d6): d 3.78-3.86 (m, 2 H, CH2), 5.97 (q,
1 H, CH), 6.96 (m, 4 Haromatic), 7.287.45 (m, 1 Haromatic), 9.08 (s, 1 Htetrazole), 10.02-10.2
(d, 1 H, NH). 13C NMR (75 MHz, acetone-d6): d 27.48 (CH2), 61.55 (CH), 108.04 (C3-
aromatic), 111.25 (CH7-aromatic), 117.64 (CH4-aromatic), 118.89 (CH5-aromatic), 121.44 (CH6-
aromatic), 123.53 (CH2-aromatic), 126.92 (Caromatic), 136.34 (Caromatic), 143.29 (CHtetrazole),
168.41 (C ¼ O).
Anal. Calcd for C12H11N5O2: C, 56.03; H, 4.31; N, 27.22. Found: C, 56.08; H, 4.25;
N, 27.14.
4-Methyl-2-(1H-tetrazol-1-yl)pentanoic acid (2d)
White crystals, mp 220-222 ꢀC; IR (KBr) 3475 (COOH), 3105 (CHtetrazole), 2961
1
(CHstretch), 1725 (C ¼ O) (cmꢂ1). H NMR (300 MHz, D2O-acetone-d6): d 0.74-1.01 (m,
6 H, 2 CH3), 1.84 (m, 1 H, CH), 5.17 (t, 1 H, CH), 9.17 (s, 1 Htetrazole). 13C NMR
(75 MHz, acetone-d6): d 21.62 (CH3), 23.28 (CH3), 25.91 (CH), 42.25 (CH2), 64.01
(CH), 144.69 (CHtetrazole), 174.00 (C ¼ O).
Anal. Calcd for C7H12N4O2: C, 45.64; H, 6.57; N, 30.42. Found: C, 45.39; H, 6.58;
N, 30.40.
3-Methyl-2-(1H-tetrazol-1-yl)butanoic acid (2e)
White crystals, mp 201-203 ꢀC; IR (KBr) 3427 (COOH), 3170 (CHtetrazole), 3097, 2969,
1
2875 (CHstretch), 1626 (C ¼ O) (cmꢂ1). H NMR (300 MHz, D2O-acetone-d6): d 1.08 (m,
6 H, 2 CH3), 2.71 (m, 1 H, CH), 5.25 (m, 1 H, CH), 9.49 (s, 1 Htetrazole). 13C NMR
(75 MHz, acetone-d6): d 18.94 (CH3), 20.25 (CH3), 24.72 (CH), 71.92 (CH), 145.06
(CHtetrazole), 173.27 (C ¼ O).
Anal. Calcd for C6H10N4O2: C, 42.35; H, 5.92; N, 32.92. Found: C, 42.39; H, 5.88;
N, 32.81.
3-(4-Hydroxyphenyl)-2-(1H-tetrazol-1-yl)propanoic acid (2f)
White crystal, mp 221 ꢀC; IR (KBr) 3445 (OH), 3265 (COOH), 3153 (CHtetrazole), 1605
1
(C ¼ O) (cmꢂ1). H NMR (300 MHz, DMSO-d6): d 3.38 (m, 3 H, CH2 & OH), 5.11 (dd,
1 H, CH), 6.58 (d, 2 Haromatic), 6.76 (d, 2 Haromatic), 9.19 (s, 1 Htetrazole). 13C NMR
(75 MHz, acetone-d6): d 37.57 (CH2), 66.13 (CH), 115.60 (2 CHo-phenol), 127.51 (Cp-phe-
nol), 129.86 (2 CHm-phenol), 143.95 (CHtetrazole), 156.79 (Cipso-OH), 171.69 (C ¼ O).

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
7
Anal. Calcd for C10H10N4O3: C, 51.28; H, 4.30; N, 23.92. Found: C, 51.22; H, 4.23;
N, 23.85.
3-(1H-imidazol-4-yl)-2-(1H-tetrazol-1-yl)propanoic acid (2g)
White crystals, mp 138-140 ꢀC; IR (KBr) 3381 (COOH & NH), 3021 (CHtetrazol), 1691
1
(C ¼ O) (cmꢂ1). H NMR (300 MHz, DMSO-d6): d 3.40 (m, 2 H, CH2), 4.70 (NH), 5.20
(dd, 1 H, CH), 6.48 (s, 1 Haromatic), 7.38 (s, 1 Haromatic), 9.22 (s, 1 Htetrazole). 13C NMR
(75 MHz, acetone-d6): d 30.32 (CH2), 64.47 (CH), 117.25 (C5 imidazole), 133.22 (C4 imid-
azole), 134.81 (CH2 imidazole), 143.44 (CHtetrazole), 174.99 (C ¼ O).
Anal. Calcd for C7H8N6O2: C, 40.39; H, 3.87; N, 40.37. Found: C, 40.25; H, 3.81;
N, 40.29.
2-(1H-tetrazol-1-yl)-5-(1H-tetrazole-1-carboximidamido)pentanoic acid (2h)
Yellow crystals, mp 183-185 ꢀC; IR (KBr) 3350 (COOH & NH2), 3117 (CHtetrazole),
1
3012, 2924, 2879 (CHstretch), 1681 (C ¼ O) (cmꢂ1). H NMR (300 MHz, DMSO-d6): d
1.43 (m, 2 H, CH2), 1.72 (2 H, CH2), 2.20 (m, 3 H, CH2 & NH), 5.02 (m, 1 H, CH), 7.88
(bs, NH2), 9.07 (bs, ¼NH), 9.41 (s, 1 Htetrazole). 13C NMR (75 MHz, acetone-d6): d 25.43
(CH2), 29.19 (CH2), 39.43 (CH2), 63.47 (CH), 143.54 (CHtetrazole), 157.35 (¼C),
171.03 (C ¼ O).
Anal. Calcd for C7H13N7O2: C, 34.29; H, 4.32; N, 49.98. Found: C, 34.30; H, 4.30;
N, 49.90.
Acknowledgment
The authors are grateful to the Bu-Ali Sina University, Hamedan, Iran, for the financial support
of this work.
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