Synthesis of 5-substituted 1H-tetrazoles using a nano ZnO/Co₃O₄ catalyst

Abstract

Zinc salts have catalytically active sites suitable for synthesis of substituted 1H-tetrazoles. Herein we report the synthesis of 5-substituted 1H-tetrazoles catalyzed by nano ZnO/Co₃O₄. This is a novel heterogeneous catalyst which showed excellent efficiency, affording good to excellent yield of products.

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Tetrazoles are a class of nitrogen containing heterocyclic compounds which are studied extensively due to their wide range of applications.¹ The importance of tetrazole and its derivatives has increased because of their use as an isosteric replacement for carboxylic acids in drug design.² The metabolically stable tetrazole group has a pK_a similar to that of –CO₂H. When it is a part of a drug molecule, it has the potential of offering a longer in vivo half-life. The presence of the tetrazole moiety in a drug molecule improves oral bioavailability and cell penetration. The angiotensin II receptor antagonist Losartan (Fig. 1) is one example where tetrazole is being used in replacement of –CO₂H.³ Application of tetrazoles involves their use in pharmaceuticals, in speciality explosives⁴ and as precursors of a variety of nitrogen containing heterocyclic compounds like imidoylazides.⁵

Fig. 1 Losartan.

Synthesis of 5-substituted 1H-tetrazoles involves [3+2] cycloaddition of an azide (NaN₃/TMSN₃) to the corresponding nitrile. Several methods have been reported for the preparation of 5-substituted 1H-tetrazoles. They suffer from various disadvantages such as the use of toxic metals, expensive reagents, explosive hydrazoic acid and severe reaction conditions.⁶ The use of stoichiometric amounts of zinc(II) salt,^7a–d metal complex,^7e CdCl₂,⁶ Fe(OAc)₂,^7f TBAF,^7g micellar media^7h and ionic liquid⁷ⁱ has sorted out the above said problems.

However these homogeneous catalysts pose difficulties in separation, recovery and reusability. Therefore many researchers have developed various heterogeneous catalyst systems, such as silica supported FeCl₃,^8a ZnS,^8b Zn/Al hydrotalcite,^8c Cu₂O,^8d antimony trioxide,^8e ZnHAP^8f and metal tungstates.^8g It was proved that the function of zinc compounds is to activate the –CN triple bond of nitriles. This activation is only due to the coordination of the nitrogen atom with the Lewis acid metal like zinc.⁹ We are interested in developing heterogeneous metal oxide catalysts for various organic transformations.¹⁰ The use of ZnO alone could not fetch good yield of the 5-substituted 1H-tetrazoles. Hence we tried to increase the acidity of zinc oxide by mixing it with other metal oxides such as TiO₂, CeO₂ and Co₃O₄. It was observed that the ZnO/TiO₂, ZnO/CeO₂ and ZnO/Co₃O₄ combinations were not explored for the synthesis of 5-substituted 1H-tetrazoles. The mixed oxide of ZnO/Co₃O₄ shows good optical and magnetic properties. The catalytic activity of Co₃O₄/ZnO was well studied for carbonylation of glycerol.¹¹ Herein we report the synthesis of nano ZnO/Co₃O₄ mixed metal oxide and its application as a heterogeneous catalyst for the synthesis of 5-substituted 1H-tetrazoles.

All the mixed metal oxides were prepared by taking a 1 : 1 mole ratio of their precursors. Nano ZnO/Co₃O₄ mixed metal oxide is synthesized by a simple precipitation method under ultrasonication. Zinc acetate and cobalt acetate in a 1 : 1 mole ratio were dissolved in 0.1 N HCl and a precipitate is obtained by dropwise addition of aqueous ammonia. The whole procedure of precipitation was carried out under ultrasonication. Titanium tetraisopropoxide and cerium nitrate were used as precursors for preparation of TiO₂ and CeO₂. The bulk metal oxides and mixed metal oxides were prepared by adding an aqueous ammonia solution to the solutions of respective precursors. This addition was carried out without ultrasonication. The pH of the solution was adjusted between 8–9.

The major phase of the obtained particle was analyzed by X-ray diffraction. Fig. 2A shows the XRD spectra of ZnO, Co₃O₄ and Nano ZnO/Co₃O₄. The XRD spectrum of ZnO is indexed to the hexagonal close packed wurtzite structure. The peaks at about 31°, 34°, 35°, 47°, 56°, 62°, 67° and 68° correspond to 100, 002, 101, 102, 110, 103, 200, and 112 crystal planes respectively.^12a The XRD spectrum of Co₃O₄ is indexed to the cubic spinels. The peaks at 31° and 37° in the spectrum of Co₃O₄ correspond to (220) and (311) planes and confirm the cubic spinel structure of Co₃O₄.^12b The prepared nano ZnO/Co₃O₄ did not show any extra peak other than the peaks observed for ZnO and Co₃O₄. EDAX analysis shown in Fig. 2B confirms that the prepared nano ZnO/Co₃O₄ is composed of zinc (40.45%), cobalt (32.41%) and oxygen (27.14%) elements only. The zinc X-ray energies are 8.63 keV (K-line) and 1.01 (L-line), the cobalt X-ray energies are 6.92 keV (K-line) and 0.77 (L-line) and the oxygen X-ray energy is 0.523 keV (K-line).

Fig. 2 XRD (A) and EDAX (B) of nano ZnO/Co₃O₄.

The FTIR spectra of the obtained Co₃O₄, ZnO and nano ZnO/Co₃O₄ are shown in Fig. 3A. In the spectrum of Co₃O₄ peaks at 663.48 cm⁻¹ and 569.39 cm⁻¹ are assigned to the ν(Co–O) modes, which confirm the formation of Co₃O₄. The broad bands at 3456 cm⁻¹ and 1626 cm⁻¹ are assigned to OH stretching and bending modes of water respectively.^12c In the spectrum of ZnO, the peak at 3497 cm⁻¹ corresponds to the vibration mode of the OH group of water. It is due to the presence of a small amount of adsorbed water on the surface of the ZnO molecule. The band at 1627 cm⁻¹ is due to the OH bending of water. Zn–O stretching is observed at 526 cm⁻¹.^12d The FTIR spectrum for nano ZnO/Co₃O₄ shows peaks at 3599 cm⁻¹ and 1646 cm⁻¹, which may be because of vibration mode of water adsorbed on the surface of the catalyst. The new peaks are observed at 1250.80 cm⁻¹ and 979.46 cm⁻¹. They may be assigned to Co bonding with ZnO, due to insertion of the Co in the ZnO structure which gives local vibration in ZnO. This is proved on the basis of the Raman spectrum. The Raman spectrum of ZnO/Co₃O₄ is shown in Fig. 3B. It is reported that if the concentration of Co in ZnO/Co₃O₄ is more than 0.2 mole fraction, the Raman active modes for ZnO are not observed. As the Co concentration increases, ZnO loses its translational symmetry and Co₃O₄ gains the translational symmetry toward F_2g symmetry. The modes related to Co are due to the secondary phase of Co₃O₄ and this indicates the local vibrations of Co in ZnO. The modes of Co₃O₄ dominate over the ZnO modes.¹³ The mole ratio of ZnO/Co₃O₄ used in the current experiment is 1 : 1 (0.5 mole fraction). The Raman active modes observed at 487 cm^–1 for E_g, 524 and 625 cm^–1 are assigned to F_2g modes of Co₃O₄. The Raman active mode observed near 709 cm^–1 appears to be due to Co doping.

Fig. 3 FT-IR of Co₃O₄, ZnO and ZnO/Co₃O₄ (A) and Raman spectra (B) of nano ZnO/Co₃O₄.

The size and shape of the nano ZnO/Co₃O₄ particles and their degree of agglomeration were obtained by TEM (Fig. 4A) and SEM (Fig. 4B and C). TEM shows that the size of nano ZnO/Co₃O₄ is in the range of 40–50 nm. The SEM image depicts that the crystals have cubic structure. TEM and SEM images are in good agreement with each other in terms of size and shape.

Fig. 4 (A) TEM, (B) SEM image of fresh ZnO/Co₃O₄ at 100 nm bar and (C) SEM image at 10 nm bar.

A model reaction was carried out by taking the mixture of benzonitrile, sodium azide and catalyst in the presence of DMF solvent. Table 1 gives the details about particle size, total acid sites and catalytic activity of ZnO, Co₃O₄, bulk ZnO/Co₃O₄ and nano ZnO/Co₃O₄ (Table 1, entries 1–4). The catalytic activity of ZnO/Co₃O₄ was found to be more because of better acidity than either ZnO or Co₃O₄.¹⁴ More interestingly Co₃O₄ has higher acidity than ZnO, but shows less catalytic activity than ZnO. This may be due to activation of the CN triple bond of the nitrile by coordination of the nitrogen atom with the Lewis acid metal like zinc. In addition, nano ZnO/Co₃O₄ shows better catalytic activity than bulk ZnO/Co₃O₄ because it has smaller particle size and hence has high surface area. Table 2 shows the comparison of the activity of the different heterogeneous catalysts with that of prepared ZnO/Co₃O₄. The comparison of the different catalysts (previously reported and used in the present study) was done by considering the quantity of the catalyst used for the reaction. We observed that the nano ZnO/Co₃O₄ catalyst gives better yield than FeCl₃/SiO₂, ZnHAP and Zn/Al-HT whereas a similar yield is obtained in the case of BaWO₃. Nano ZnO/Co₃O₄ proved to be a better catalyst than BaWO₃ with respect to recyclability. Table 3 gives the details of optimized conditions of the model reaction. It can be seen that 95% yield of the product is obtained at 140 °C whereas 90% yield is obtained at 120 °C. Since there is a very marginal difference in the yield, all the reactions are carried out 120 °C. Prolonged heating beyond 12 h did not show significant increase in the yield of the desired product.

Table 1 Influence of the catalyst on synthesis of 1H-tetrazoles^a

Sr. No.	Catalyst	Size	Tot. no. of acid sites		Yield^b (%)
			mL g^−1	mmol g^−1
a Reaction conditions: 1 mmol benzonitrile, 1.5 mmol NaN3, 50 mg catalyst and 3 ml DMF for 12 h at 120–130 °C. b Isolated yield.
1	No catalyst	—	—	—	0
2	ZnO	19 μm	1.3377	0.0548	45
3	TiO2	53 μm	—	—	10
4	CeO2	73 μm	—	—	41
5	Co3O4	2 μm	2.4814	0.1017	31
6	ZnO/TiO2	444 μm	—	—	5
7	ZnO/CeO2	56 μm	—	—	58
8	ZnO/Co3O4	18 μm	—	—	80
9	Nano ZnO/Co3O4	40–50 nm	4.5352	0.1859	90

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Table 2 Comparison of various heterogeneous catalysts

Sr. No.	Catalyst	Time/h	Temp/°C	Yield (%)	Reference
a Yield after the third cycle. b Yield after the fourth cycle.
1	FeCl3/SiO2	12	120	79	8a
2	ZnHAP	12	120–130	78	8f
3	BaWO4	12	120	90, 73^a	8g
4	Zn/Al-HT	12	120–130	84	8c
5	Nano ZnO/Co3O4	12	120	90, 84^b	Present work

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Table 3 Influence of the various optimised conditions on synthesis of 1H-tetrazoles^a

Sr. No.	Catalyst (mg)	Time/h	Temp/°C	Solvent	Yield^b (%)
a Reaction conditions: 1 mmol benzonitrile, 1.5 mmol NaN3, and 3 ml solvent. b Isolated yield. c Catalyst after four cycles.
1	50	24	120	DMF	90
2	50	18	120	DMF	90
3	50	12	120	DMF	90
4	50	6	120	DMF	55
5	50	12	80	DMF	14
6	50	12	100	DMF	30
7	50	12	140	DMF	95
8	50	12	120	DMSO	49
9	50	12	120	NMP	75
10	50	12	120	H2O	≤10
11	40	12	120	DMF	70
12	30	12	120	DMF	62
13	20	12	120	DMF	38
14	10	12	120	DMF	33
15	50	12	120	DMF	83^c

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Solvent has a remarkable effect on the yield of the desired product. DMF was found to be the most suitable solvent giving a maximum yield of 90% whereas NMP and DMSO gave 75% and 49% yield respectively. Nano ZnO/Co₃O₄ also showed good recyclability for four cycles giving 83% of product yield.

To study the scope and applicability of the developed protocol, different benzonitriles were used as the starting material and the results are shown in Table 4. The results show that all nitriles react efficiently with sodium azide and give excellent yield of desired products. The presence of an electron donating group at the para position gave an excellent yield of more than 92% (Table 4, entries 3–5). The reactions of benzonitrile having an electron withdrawing group at the para position gave a similar yield (Table 4, entry 2). Thus, the observations suggest that an electron donating group or an electron withdrawing group on benzonitrile does not have a notable effect and gives good to excellent yield.

Table 4 Nano ZnO/Co₃O₄ catalysed synthesis of 5-substituted 1H-tetrazoles^a

Sr. No.	Substrate	Product	Yield^b (%)
a Reaction conditions: 1 mmol benzonitrile, 1.5 mmol NaN3, and 3 ml solvent. 50 mg catalyst at 120–130 °C for 12 h. b Isolated yield.
1			90
2			84
3			94
4			92
5			93

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In conclusion, we have prepared nano ZnO/Co₃O₄ as a novel catalyst for 5-substituted 1H-tetrazoles from nitriles and sodium azide. This nano sized heterogeneous catalyst showed excellent catalytic activity than ZnO or Co₃O₄. The given methodology is efficient and environmentally benign. This recyclable catalyst offers advantages like simple work-up and high yields. The developed concept is expected to be more general and easily applicable.

The authors are thankful to UGC-Green Technology Centre, New Delhi, India, for awarding the fellowship.

Notes and references

1. R. N. Butler, in Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon, Oxford, UK, 1996, vol. 4.
2. R. Herr, Bioorg. Med. Chem., 2002, 10, 3379.
3. B. C. Bookser, Tetrahedron Lett., 2000, 41, 2805.
4. (a) V. A. Ostrovskii, M. S. Pevzner, T. P. Kofmna, M. B. Shcherbinin and I. V. Tselinskii, Targets Heterocycl. Syst., 1999, 3, 467; (b) M. Hiskey, D. E. Chavez, D. L. Naud, S. F. Son, H. L. Berghout and C. A. Bome, Proc. Int. Pyrotech. Semin., 2000, 27, 3.
5. (a) R. Huisgen, J. Sauer, H. J. Sturn and J. H. Markgraf, Chem. Ber., 1960, 93, 2106; (b) D. J. Moderhack, J. Prakt. Chem., 1988, 340, 687; (c) A. R. Modarresi-Alam, H. Keykha, F. Khamooshi and H. A. Dabbagh, Tetrahedron, 2004, 60, 1525; (d) A. R. Modarresi-Alam, H. Keykha, F. Khamooshi, M. Rostamizadeh, M. Nasrollahzadeh, H. R. Bijanzadeh and E. Kleinpeter, J. Mol. Struct., 2007, 841, 67.
6. G. Venkateshwarlu, A. Premalatha, K. C. Rajanna and P. K. Saiprakash, Synth. Commun., 2009, 39, 4479.
7. (a) Z. P. Demko and K. B. Sharpless, J. Org. Chem., 2001, 66, 7945; (b) Z. P. Demko and K. B. Sharpless, Org. Lett., 2002, 4, 2525; (c) O. G. Mancheño and C. Bolm, Org. Lett., 2007, 9, 2551; (d) L.-Z. Wang, Z.-R. Qu, H. Zhao, X.-S. Wang, R.-G. Xiong and Z.-L. Xue, Inorg. Chem., 2003, 42, 3969; (e) L. Bosch and J. Vilarrasa, Angew. Chem., 2007, 119, 4000; (f) J. Bonnamour and C. Bolm, Chem.–Eur. J., 2009, 15, 4543; (g) D. Amantini, R. Beleggia, F. Fringuelli, F. Pizzo and L. Vaccaro, J. Org. Chem., 2004, 69, 2896; (h) B. S. Jursic and B. W. Leblanc, J. Heterocycl. Chem., 1998, 35, 405; (i) B. Schmidt, D. Meid and D. Kieser, Tetrahedron, 2007, 63, 492.
8. (a) D. Habibi and M. Nasrollahzadeh, Synth. Commun., 2010, 40, 3159; (b) L. Lang, B. Li, W. Liu, L. Jiang, Z. Xu and G. Yin, Chem. Commun., 2010, 46, 448; (c) M. Lakshmi Kantam, K. B. Shiva Kumar and K. Phani Raja, J. Mol. Catal. A: Chem., 2006, 247, 186; (d) T. Jin, F. Kitahara, S. Kamijo and Y. Yamamoto, Tetrahedron Lett., 2008, 49, 2824; (e) G. Venkateshwarlu, K. C. Rajanna and P. K. Saiprakash, Synth. Commun., 2009, 39, 426; (f) M. Laxmi Kantam, V. Balasubramanyam and K. B. Shiva Kumar, Synth. Commun., 2006, 36, 1809–1814; (g) J. He, B. Li, F. Chen, Z. Xu and G. Yin, J. Mol. Catal. A: Chem., 2009, 304, 135.
9. (a) F. Himo, Z. P. Demko and L. Noodleman, J. Org. Chem., 2003, 68, 9076; (b) F. Himo, Z. P. Demko, L. Noodleman and K. B. Sharpless, J. Am. Chem. Soc., 2002, 124, 12210; (c) F. Himo, Z. P. Demko, L. Noodleman and K. B. Sharpless, J. Am. Chem. Soc., 2003, 125, 9983.
10. (a) S. M. Agawane and J. M. Nagarkar, Tetrahedron lett., 2011, 52, 3499–3504; (b) S. M. Agawane and J. M. Nagarkar, Tetrahedron lett., 2011, 52, 5220–5223.
11. (a) E. Kandjani, S. E. Hashemi Amiri, M. R. Vaezi and S. K. Sadrnezhaad, J. Optoelectron. Adv. Mater., 2010, 12, 2057–2062; (b) F. Rubio-Marcos, V. Calvino-Casilda, M. A. Banares and J. F. Fernandez, J. Catal., 2010, 275, 288–293.
12. (a) Y. Tak and K. Yong, J. Phys. Chem. C, 2008, 112, 74; (b) Y.-P. Yang, K.-L. Huang, R.-S. Liu, L.-P. Wang, W.-W. Zeng and P.-M. Zhang, Trans. Nonferrous Met. Soc. China, 2007, 17, 1082; (c) D. Zou, C. Xu, H. Luo, L. Wang and T. Ying, Mater. Lett., 2008, 62, 1976; (d) N. Faal Hamedani and F. Farzaneh, J. Sci., Islamic Repub. Iran, 2007, 17, 23.
13. R. Bhargava, P. K. Sharma, S. Kumar, A. C. Pandey and N. Kumar, J. Raman Spectrosc., 2011, 42, 1802–1807.
14. See TPD in ESI†.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cy20094e

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