TiCl3 catalyzed one-pot protocol for the conversion of aldehydes into 5-substituted 1H-tetrazole

Article abstract of DOI:10.1016/j.tetlet.2018.08.050

An efficient protocol has been explored for the one-pot synthesis of tetrazole derivatives with wide functional group compatibility in moderate to very high yields starting from aliphatic and aromatic substituted aldehydes. The reaction proceeds via non-isolated oxime and nitrile intermediates. The structures of the products were confirmed by IR and NMR spectroscopy. A plausible reaction mechanism is also provided.

Full text of DOI:10.1016/j.tetlet.2018.08.050

Accepted Manuscript
TiCl3 catalyzed one-pot protocol for the conversion of aldehydes into 5-substi-
tuted 1H- tetrazole
Rakesh Ranjan Chakraborty, Pranab Ghosh
PII:
S0040-4039(18)31051-7
https://doi.org/10.1016/j.tetlet.2018.08.050
TETL 50225
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 July 2018
24 August 2018
26 August 2018
Please cite this article as: Ranjan Chakraborty, R., Ghosh, P., TiCl3 catalyzed one-pot protocol for the conversion
of aldehydes into 5-substituted 1H- tetrazole, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.08.050
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TiCl3 catalyzed one-pot protocol for the conversion of aldehydes into 5-substituted 1H-
tetrazole
Rakesh Ranjan Chakraborty and Pranab Ghosh*
Department of Chemistry, University of North Bengal, Dist. Darjeeling, West Bengal, India
Tel :+91 (0353) 2776381 ; fax: +91 (0353) 2699001.
E mail: pizy12@yahoo.com (P.Ghosh).
Abstract: An efficient protocol has been explored for the one-pot synthesis of tetrazole
derivatives with wide functional group compatibility in moderate to very high yields starting
from aliphatic and aromatic substituted aldehydes. The reaction proceeds via non-isolated oxime
and nitrile intermediates. The structures of the products were confirmed by IR and NMR
spectroscopy. A plausible reaction mechanism is also provided.
Keywords: Aldehyde, Hydroxylamine hydrochloride, 5-substituted-1H-tetrazole, sodium azide,
TiCl3, cycloaddition reaction.
Introduction
Tetrazoles are a class of heterocycles which are receiving considerable attention due to wide
range of applications associated with it and the literature having tetrazole chemistry are growing
rapidly.[1] .Tetrazoles are reported to possess a huge biological activities such as antifungal[2],
antibacterial [3], analgesic[4], antiviral, anti-inflammatory, antiulcer [5], and antihypertensive
activities[6].Synthetic tetrazole derivatives have also been reported to possess antidiabetic[7],
anti-HIV[8] activities and used for treatment of asthma[9]. 5-substituted-1H-tetrazoles can act as
lipophilic spacer and carboxylic acid surrogates[10] and used in explosives[11], function as
ligands in coordination chemistry[12].In addition, some famous drugs (Fig.1) Pemiroplast,
candesartan, valsartan, losartan, and zolarsartan[13] contain tetrazolyl moieties. Traditional
synthesis of 5-substituted 1H-tetrazole has been reported to proceed via [3+2] cycloaddition of

azide ion with nitrile[14].This procedure suffers from a few drawbacks, e.g. expensive and toxic
metal organic azide and nitrile and probability of forming hydrazoic acid which is explosive.
There are several catalyst in literature ,e.g. BF3.OEt2[15], Pd(OAc)2/ZnBr2[16], AlCl3[17],
Yb(OTf)3[18] etc, but there are still a few drawbacks, e.g, tedious separation and recovery of the
catalysts.Recently several heterogeneous catalytic system such as nanocrystalline ZnO, Zn/Al
HT[19], FeCl3/SiO2, [20], Cu2O[21], CdCl2 [22], metal-modified montmorillonites and zeolite
were extensively reported[23]. Many metals, such as Fe, Cu, Mo, V, Zn, Al, Mn, Co were used
to improve the effectiveness of montmorillonites[24-31]. These methods also have some
drawbacks, such as, these require excess amount of sodium azide, long reaction time, in spite of
that, the cycloaddition is too slow to be practically useful except strong electron withdrawing
groups activate the nitrile group. Due to the wide applications of the tetrazole-embedded
structures, easy and economical synthetic protocols are still worth exploring[32]. One-pot
protocols are particularly important as they get off the isolation of intermediate products
[33].One-pot protocols for the synthesis of tetrazole have already been reported in literature
using ammonia and iodine [34]. But this methodology should be avoided because this could
result in the formation of hydrazoic acid and triiodide monoamine, which are explosive
[35].Oximes also undergo [3+2] cycloaddition with sodium azide (NaN3) to form 5-substituted
1H-tetrazole by copper acetate as a catalyst [36].

N
N
N
Cl
N
N
H
HO
Bu
N N
NH
N
N
N
O
N
N
N
N
N
N
O
H
O
OH
Pemiroplast
Losartan
Valsartan
Fig.1. Pharmacologically important tetrazole drugs
In view of the availability, lower toxicity and ease of handling of aldehydes as compared to
nitriles, the application of aldehydes for the synthesis of tetrazole derivatives are highly attractive
and advantageous strategy. Direct transformation of aldehydes to the corresponding tetrazoles
via [3+2] cycloaddition is well documented in literature [37-38].Titanium, a very abundant,
inexpensive and nontoxic element, has been rarely utilized in organic synthesis. Out of several
titanium compounds, a few of them (TiCl4, TiCl3, TiCl2(OR)2, Cp2TiCl2, etc.) are widely used
[39]. To the best of our knowledge, TiCl3 has been not yet used for the synthesis of 5-substituted
1H-tetrazole.
In this connection, herein, we report the protocol, where we used less expensive and easily
available starting material aldehydes along with hydroxylamine hydrochloride and sodium azide
catalysed by Titanium trichloride resulting in the formation of a number of tetrazole derivatives
(1-16) from moderate to excellent yield (Table 4). Water solubility of catalyst, low toxicity, easy
work-up, low duration and excellent yield of the products are special feature of this
methodology.

TiCl3
N N
R-CHO + NH2OH + NaN3
N
R
N
DMF, reflux
H
Scheme 1. TiCl3 catalyzed one-pot protocol for the conversion of aldehydes into 5-substituted
1H- tetrazole
OH
H
O
N N
N
R-CN
N
R
H
R
N
R
H
Scheme 2. Proposed reaction intermediate for the synthesis of 5-substituted 1H-tetrazole
Results and discussion: The synthesis of tetrazoles (1-16) was achieved by the addition of
hydroxylamine hydrochloride, sodium azide, Titanium tri chloride in DMF to various aldehydes
and heating at reflux condition to afford the corresponding tetrazoles ( Scheme 1) after work-up
under acidic condition. The effect of temperature (Table1), solvent (Table 2) and amount of
catalyst (Table 3) were monitored. It was found that DMF was the best solvent (entry 4, Table 2).
We also optimized the amount of catalyst and it was found to be 20 mol% (entry 4, Table 3). For
the generalization of the reaction, we applied optimized condition i.e. hydroxylamine
hydrochloride (1.2 mmol), sodium azide (1.5 mmol) and TiCl3 catalyst (20 mol %) under reflux
condition to different aldehyde (1mmol) and got 42-95% yield at 3.5-6h (Table 4). This strategy
applies to all types of aldehydes (aliphatic, aromatic and heterocyclic). The best result was found
for aldehydes having electron withdrawing groups. The direct transformation of aldehydes into
nitriles is well documented in literature with different reaction conditions [40-42]. Spectroscopic
data confirmed the formation of the expected products. The intermediate nitrile is formed first
(Scheme 2) and then [3+2] cycloaddition reaction takes place between nitrile and azide ion.

TiCl3 facilitate the cycloaddition reaction because in absence of TiCl3, only nitrile is formed
(Table 3, entry 6).Formation of nitrile was confirmed by conducting the reaction using 3-nitro
benzaldehyde without adding NaN3 and got 83% nitrile.Completion of reaction was tested by
TLC and after acidic work-up, the desired products were achieved by column chromatography
using pet ether and ethyl acetate mixture as eluent.
Table 1: Effect of temperature on the synthesis of 5-substituted 1H-tetrazolea
Temperature(0C)
Yieldb (%)
Entry
1
2
3
Room temp
Nil
60
25
62
100
4
130
95
5
reflux
95
aReaction condition: benzaldehyde (1mmol), hydroxylamine hydrochloride
(1.2 mmol), sodium azide (1.5mmol), DMF (5ml), TiCl3 catalyst (20mol%)
at reflux condition for 4h, bIsolated yield
Table 2: Effect of solvent on the synthesis of 5-substituted 1H-tetrazolea
Yieldb (%)
Entry
Solvent
1
2
3
None
DMSO
H2O
Nil
60
20
4
5
6
7
DMF
95
Acetonitrile
Toluene
THF
30
Nil
Nil

aReaction condition: benzaldehyde (1mmol), Hydroxylamine hydrochloride (1.2mmol), sodium
azide(1.5mmol), DMF(5ml), TiCl3 catalyst (20mol%) at reflux condition for 4h, bIsolated yield
of product
Table 3: Effect of catalyst loading for the synthesis of 5-substituted 1H-tetrazolea
Yieldb (%)
Entry
Catalyst (mol%)
1
2
3
5
40
10
15
67
95
4
20
95
5
30
96
6
none
nitrile
aReaction condition: benzaldehyde (1mmol), Hydroxylamine hydrochloride (1.2mmol), sodium
azide (1.5mmol), DMF (5ml), TiCl3 catalyst at reflux condition for 4h, bIsolated Yield of Product
Table 4: Synthesis of 5-substituted 1H-tetrazole derivativesa
Entry
1
Reactant
Time(h) Product
4
Yield(%)b
86
N
N
N
CHO
N
H
2
3
4
3.5
84
95
61
N
N
N
CHO
N
O2N
H
O2N
3
N
N
N
CHO
N
H
NO2
NO2
4
N
N
CHO
NO2
N
N
H
NO2

5
5
74
N
N
CHO
OH
N
N
H
OH
6
7
8
4
5
76
71
92
N
N
CHO
N
N
HO
HO
H
HO
N
CHO
N
N
N
H
HO
OCH3
OCH3
3.5
N
CHO
N
N
N
F
H
F
9
3
5
89
52
75
82
85
79
N
CHO
N
N
N
H
Cl
Cl
10
11
12
13
14
N
N
CHO
Cl
N
N
H
Cl
5
N
CHO
N
N
N
MeO
H
MeO
5.5
3.5
3
N
CHO
CHO
N
N
N
H
Me2N
Me2N
N
N
N
N
H
N
N
N
CHO
N
O
O
H

15
16
6
4
42
81
N
N
N
CHO
N
H
N
N
CHO
N
N
H
aAldehyde (1mmol), hydroxylamine hydrochloride (1.2 mmol), sodium
azide (1.5 mmol) and Titanium trichloride (20mol%) in DMF( 5ml) under
reflux condition, bIsolated yield
In summary, present methodology shows the synthesis of a nitrogen rich, bio-active heterocycle
5-substituted 1H-tetrazole directly from aldehyde, hydroxylamine hydrochloride and sodium
azide catalyzed by titanium trichloride under reflux condition. The reaction is straightforward,
less time consuming and easy to handle, moreover the reaction proceeds through some non-
isolable reaction intermediates and products with excellent yield.
Conclusion
In conclusion, we have explored a lewis-acid, titanium trichloride catalyzed one-pot facile
synthesis of 5-substituted 1H-tetrazole from easily available aldehyde (aromatic, aliphatic,
heterocyclic), hydroxylamine hydrochloride and sodium azide under reflux condition.
Advantages of this methodology are, use of less harmful organic solvent and low toxic catalyst,
which are water soluble and thus causes less environmental pollution, easy work-up process and
excellent yield of products.
General procedure for the synthesis
Aldehyde (1mmol), hydroxylamine hydrochloride (1.2mmol), sodium azide (1.5mmol) and
titanium trichloride (20 mol%) were added to 5ml DMF and the mixture was kept on reflux for
requisite time (Table 4). The progress of reaction was monitored by TLC and after completion of
reaction, the mixture was treated with HCl (5ml dil.HCl), thereafter the mixture was added to

100ml water and extracted with ethylacetate, washed by water a few times. The extract was dried
over anhydrous Na2SO4, purified by column chromatography on silica-gel (60-120 mesh) by pet-
1
ether and ethyl acetate (75:25) as eluent. All the products were characterized by H NMR and
13C NMR spectroscopy.
Acknowledgements
Author is grateful to UGC New Delhi for financial support.
References
1.(a). Butler, R. N.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds.Comprehensive
Heterocyclic Chemistry; Pergamon Press: Oxford UK, 1996; Vol. 4, p 905. (b). Mohammad A
A, Moaddeli A. New J. Chem., 2015; 39: 2116-2122;
2. Sangal S K, Kumar A. J. Indian Chem. Soc. 1986; 63: 351-356;
3. Okabayashi T, Kano H, Makisumi Y. Chem. Pharm. Bull. 1960; 8: 157-161;
4. Maxwell JR, Wasdahl DA, Wolfson AC, Stenberg V I. J. Med. Chem. 1984; 27: 1565-1570;
5. Ostrovskii V, Trifonov R, Popova E. Russ Chem Bull. 2012; 61: 768-780;
6. Smith R D, Duncia J V, Lee R J, Christ D D, Chiu A T, Carini D J, Herblin W F, Timmermans
P B. M. W. M.; Wexler R R, Wong P C. Methods Neurosci. 1993; 13: 258-280;
7. Momose Y, Maekawa T, Odaka H, Ikeda H, Sohda T. Chem. Pharm. Bull. Jpn.
2002; 50: 100–111;
8. Pais G C G, Zhang X, Marchand C, Neamati N, Cowansage K, Svarovskaia
E S, Pathak V K, Tang Y, Nicklaus M, Pommier Y, Burke T R. J. Med. Chem.
2002; 45: 3184–3194;
9. Gaponik P N, Voitekhovich S V, Ivashkevich O A. Russ. Chem. Rev. 2006; 75: 507–539;
10. Singh H, Chala A S, Kapoor V K, Paul D, Malhotra R K. Prog. Med. Chem. 1980; 17: 151-
183;
11. Singh RP, Verma RD, Meshri DT, Shreeve JNM. Angew. Chem. Int. Ed. 2006; 45: 3584–
3601;
12. Mukhopadhyay S J, Lasri MFC. Guedes da Silva MA, Janua´ rio Charmier AJ, Pombeiro L.
Polyhedron. 2008; 27: 2883–2888;

13. Alonen A, Jansson J, Kallonen S, Kiriazis A, Aitio O, Finel M, Kostiainen R. Bioorg. Chem.
2008; 36:148–155;
14. Hantzsch A, Vagt A, Justus Liebigs Ann.Chem. 1901; 314: 339-369;
15. Kumar A, Narayanan R, Shechter H. J. Org. Chem. 1996; 61: 4462-4465;
16. Yizhong Z, Yiming R, Chun C. Helv. Chim. Acta. 2009; 92: 171-175;
17. Matthews D P, Green J E, Shuker A J. J. Comb. Chem. 2000; 2: 19-23;
18. Su W K, Hong Z, Shan W G, Zhang X X. Eur. J. Org. Chem. 2006;12: 2723-2726;
19. Kantam M L, Shiva Kumar K B, Raja K P. J. Mol. Catal. A: Chem. 2006; 247: 186-188;
20. Nasrollahzadeh M, Bayat Y, Habibi D, Moshaee S. Tetrahedron Lett. 2009; 50: 4435-4438;
21. Jin T, Kitahara F, Kamijo S, Yamamoto Y. Chem. Asian J. 2008; 3: 1575-1580;
22. Venkateshwarlu G, Premalatha A, Rajanna K C, Saiprakash P K. Synth. Commun. 2009; 39:
4479-4485;
23. Nasrollahzadeh M, Habibi D, Shahkarami Z, Bayat Y. Tetrahedron. 2009; 65: 10715-10719;
24. Clark P D, Mesher S T E, Primak A, Yao H. Catal. Lett. 1997; 43: 79-82;
25. Ben Achma R, Ghorbel A, Dafinov A, Medina F. Appl. Catal., A 2009; 349: 20-28;
26. Caudo S, Centi G, Genovese C, Perathoner S. Appl. Catal., B 2007; 70: 437-446;
27. Gue’lou E, Barrault J, Fournier J, Tatibouet J M. Appl. Catal. B 2003; 44, 1-8;
28. Varma R S. Tetrahedron. 2002; 58: 1235-1255;
29. Caudo S, Centi G, Genovese C, Perathoner S. Appl. Catal., B 2007; 70: 437-446;
30. Shinde A B, Shrigadi N B, Samant S D. Appl. Catal., A 2004; 276: 5-8;
31. RamaV, Kanagaraj K, Pitchumani K. J. Org. Chem. 2011; 76: 9090-9095;
32. Rodriguez F, Fananas F J. Synlett. 2013; 24: 1757–1771;
33. Fache F, Muselli M, Piva O. Synlett. 2013; 24: 1781–1784;
34. Shie J J, Fang J M. J. Org. Chem. 2007; 72: 3141–3144
35. Silberrad O. J. Chem. Soc. Perkin Trans. 1905; 1: 55–66;
36. Patil UB, Kumthekar KR, Nagarkar JM. Tetrahedron Lett. 2012; 53: 3706-3709;

37. Sridhar M, Mallu KKR, Jillella R, Godala KR, Beeram CR, Chinthala N. Synthesis. 2013;
45: 507–510;
38. Heravi MM, Fazeli A, Oskooie HA, Beheshtiha YS,Valizadeh H. Synlett .2012; 23: 2927–
2930;
39. Reetz, M. T. Organotitanium Reagents in organic synthesis; Springer Verlag, Berlin 1986.
40. Eshghi H, Gordi Z. Phosphorus, Sulfur Silicon Relat. Elem. 2005; 180: 619–623;
41. Bagherzade G, Zali A, Shokrolahi A. Chin. Chem. Lett. 2015; 26: 603–606;
42. Ghosh P , Subba R. Tetrahedron Letters. 2013; 54: 4885-4887;
Graphical Abstract
TiCl3 catalyzed one-pot protocol for the conversion of aldehydes to 5-substituted 1H- tetrazole
Rakesh Ranjan Chakraborty and Pranab Ghosh*
TiCl3
N N
R-CHO + NH2OH + NaN3
N
R
N
DMF, reflux
H
R= aryl, aliphatic, heterocyclic
HIGHLIGHTS
 Simple multi-component reaction for preparation of 5-substituted 1H-tetrazole from
economical and easily available substrate
 Shorter reaction time
 Easy reaction set-up
 Inexpensive, reusable catalyst easily separable by simple filtration
 Functional group tolerance