Tetrazoles Synthesis Essay

1. Introduction

Tetrazole is a heterocyclic compound containing a carbon atom and four nitrogen atoms in a five-membered ring. Theoretically there are three precursor tetrazole isomers: i.e., 1H-tetrazole (1), 2H-tetrazolium (2) and 5H-tetrazole (3) (Figure 1). Substituted tetrazoles exist as a nearly 1:1 ratio of 1H- and 2H-tautomeric forms. Previous studies had shown that the two positional isomers 1 and 2 may be differentiated on the nuclear magnetic resonance (NMR) timescale [1].

Figure 1. Structures of the regioisomeric tetrazole rings.

Figure 1. Structures of the regioisomeric tetrazole rings.

Like other azole compounds, due to the relatively late start of the synthesis and study of tetrazole compounds, they did not attracted much attention in the beginning. Since 1885, when Bladin first synthesized tetrazole derivatives (2-cyanophoric-5-phenyltetrazole) to 1950, only some 300 kinds of derivatives were reported [2]. Since the 1950s, when tetrazole compounds became widely used in agriculture, biochemistry, medicine, pharmacology, explosives and other aspects, research began to develop rapidly [3,4]. The tetrazolyl functional group which was often considered as a carboxylic acid replacement in drugs, not only because the pKa is close, but it also has approximately the same planar delocalized system space requirements, and it provided a maximum nitrogen content of any heterocyclic compound [5]. The planar ring skeleton structure and the nitrogen-rich multi-electron conjugated system confer tetrazole derivatives with both donor and acceptor electronic properties. Tetrazole and its derivatives have this attracted the interest of scientists because of their unique structures and their potential applications as antihypertensive, anti-allergic, antibiotic and anticonvulsant agents [6,7,8,9]. In the present review, emphasis was focused on the diverse pharmacological properties associated with substituted tetrazoles in the past few years and a conclusive discussion on structure-activity relationship (SAR) of these compounds is provided.

2. Preparation of Tetrazole Derivatives

Several methods for the synthesis of tetrazoles are widely reported in the literature. The main synthetic routes to tetrazoles are outlined in Scheme 1, Scheme 2 and Scheme 3. Tetrazoles could be synthesized by the reaction of substituted amines 4 with triethyl orthoformate and sodium azide in dimethyl sulfoxide (DMSO) [10,11] (Scheme 1). A new method to convert substituted amines into tetrazoles involves preparing functionalized superparamagnetic Fe3O4·SiO2 possessing high saturation magnetization [12].

Scheme 1. Synthesized route 1 for tetrazoles.

Scheme 1. Synthesized route 1 for tetrazoles.

The [3+2] cycloaddition between hydrazoic acid and cyanide derivatives is well known as an efficient route (Scheme 2). We can thus get substituted tetrazoles 5 from isocyanides 6. The reaction of 6 and azidotrimethylsilane (1.5 equiv.) was conducted in MeOH (0.5 M) in the presence of a catalytic amount of HCl (2 mol %, 1.0 M in Et2O solution) at 60 °C [13,14]. One of the main procedures frequently used for the preparation of 5-substituted tetrazoles 7 involves heating a suspension of 6, sodium azide, ammonium chloride and lithium chloride (1.20 g, 28 mmol) in anhydrous dimethylformamide (DMF) under stirring at 110 °C [15,16,17]. Compound 7 was also obtained in a sealed pressure vessel reaction where NaN3 dissolved in H2O, compound 6, ammonium chloride, ammonium fluoride and propane-1,2-diol (DPOL) were stirred and heated for 48 h [18]. Aryloxy tetrazoles were commonly prepared by the reaction of phenols with cyanogen bromide in the first step. Then sodium azide was added into refluxing acetone-water [19]. The most convenient route to 5-substituted-1H-tetrazoles 8 is the reaction of azide ion with nitriles [20]. The literature is full of examples of this conversion method. They can be divided into three main categories using tin or silicon azides [21], acidic media [22], and strong Lewis acids [23,24]. In addition, all of the known methods use organic solvents, in particular, dipolar aprotic solvents such as DMF [25]. A new method for the synthesis of 5-substituted-1H-tetrazoles method was reported where compound 6, water, sodium azide and zinc chloride were refluxed in a hood [26,27,28].

Scheme 2. Synthesized route 2 for tetrazoles.

Scheme 2. Synthesized route 2 for tetrazoles.

Reagents and Conditions: a: MeOH, HCl, 60 °C; b: (1) NaN3, NH4Cl, LiCl, DMF, 110 °C; (2) NaN3, NH4Cl, NH4F, DPOL, 48 h; c: N3, CN.

If one wants to prepare 1,5-disubstituted-tetrazoles from the corresponding amide, there are many routes (Scheme 3). First, one can prepare an oxyphosphonium salt under Mitsunobu conditions from the corresponding amide, followed with reaction with trimethylsilyl azide leading to the desired 1,5-disubstituted-tetrazoles. This method proves to be especially useful for applications when an N-protected tetrazole is required. Preservation of chirality in the synthesis of a tetrazole analogue of an amino acid (phenylalanine) was demonstrated [29]. In addition to the above direct approach, we can also through multiple steps to generate 1,5-disubstituted tetrazoles. Usually compounds 9 can be converted to compounds 10 with phosphorus oxychloride (POCl3) and thionylchloride (SOCl2) [30]. Compounds 11 can also be prepared in suitable yields by reaction of compounds 9 with Lawesson’s reagent or phosphorus pentoxide [31]. 1,5-Disubstituted tetrazoles can also be synthesized by reacting compounds 10 with triethyl orthoformate and sodium azide [32]. Compounds 12 can be synthesized by the reaction of compounds 10 and compounds 11 with hydrazine hydrate [33,34]. 1,5-Disubstituted tetrazoles can finally be synthesized by reacting 12 with CH3COOH and aqueous NaNO2 under ice-bath conditions, making sure that the reaction temperature is below 5 °C [35,36].

Scheme 3. Synthesized route 3 for tetrazoles.

Scheme 3. Synthesized route 3 for tetrazoles.

Reagents and Conditions: d: oxyphosphonium salt, C3H9N3Si; e: POCl3, SOCl2; f: Lawesson’s reagent/P2O5; g: HC(OC2H5)3, NaN3; h: N2H4·H2O; i: CH3COOH, NaNO2, below 5 °C.

There are some ways to get 2,5-disubstituted-tetrazoles. One of the most efficient routes (Scheme 4) uses lithium trimethylsilyldiazomethane (15) prepared from TMSCHN2 and lithium diisopropylamide (LDA), which reacts smoothly with the methyl esters of carboxylic acids at 0 °C to give compounds 16 in good yields [37].

Scheme 4. The most efficient route for synthesis of 2,5-disubstituted-tetrazoles.

Scheme 4. The most efficient route for synthesis of 2,5-disubstituted-tetrazoles.

Scheme 5. Synthesized routes for compounds 18–22.

Scheme 5. Synthesized routes for compounds 18–22.

When the hydrazides 17 were treated with thionyl chloride, the corresponding hydrazidoyl compounds 18 were obtained (Scheme 5). Next the reaction of compounds 18 with phenylhdyrazine was examined to prepare the hydrazidines 19 which can be oxidized to formazan derivatives 20. 2,5-Disubstituted tetrazoles 21 can be synthesized by reacting compounds 20 with potassium carbonate [38]. Compounds 20 also can be synthesized from compounds 22 [39].

3. Biological Activity of Tetrazolium Derivatives

Compounds derived from tetrazolium have received particular attention due to their pharmacological properties. Numerous studies have been published on the antibacterial and antifungal properties of these derivatives. Furthermore, these compounds also present anti-inflammatory, analgesic, anticancer, anticonvulsant, antihypertensive, hypoglycemic, antiparasitic, and antiviral activities. The aforementioned properties and the possibility to attach several structurally distinct substituents to the heterocycle ring to modify either the biological or physico-chemical properties of these compounds have prompted the use of this heterocycle as a template in many research programs aimed at the development of new bioactive compounds.

3.1. Antibacterial and Antifungal Activity

7,9-Disubstituted-7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines (Figure 2) were synthesized and evaluated for their antibacterial activity. Compound 23 exhibited better activity than ampicillin against all the tested cultures, except S. aureous [40]. A novel series of tetrazole compounds were reported to possess antimicrobial activity in vitro by the disc diffusion method measuring zones of inhibition. The results of the study showed that the synthesized compound 2-methyl-3-{4-[2-(1H-tetrazol-5-yl-ethylamino]phenyl}-3H-quinazolin-4-one (24) displayed fairly good antimicrobial activity against the test organisms, although the activity was less than that of the reference drugs (ciprofloxacin and fluconazole, respectively) [41]. It was reported that a series of new 5-thio-substituted tetrazole derivatives were synthesized and antimicrobial screening showed that all the synthesized compounds showed moderate activity against the tested organisms. Among the newly synthesized compounds, 25 and 26 showed the most effective antibacterial and antifungal activities. The study suggested that further work with similar types of analogues was clearly warranted [42].

Figure 2. Structures of compounds 2326.

Figure 2. Structures of compounds 2326.

A variety of heterocyclic tetrazole derivatives were synthesized (Figure 3). Among the synthesized compounds, compounds 27, 28, 29, 30, 31 and 32 exhibited antimicrobial activities with minimal inhibitory concentration (MIC) values ranging from 23.40 to 46.87 μg/L. Molecular modeling results were in accordance with the in vitro antimicrobial screening. The SAR research results showed that pyran derivatives were more active than pyridine derivatives and the activity order for the R substituent was: 4-OMe> 4-Me > 3-OH > H > 4-Cl > 4-NO2 [43].

Figure 3. Structures of compounds 2732.

Figure 3. Structures of compounds 2732.

A new series of oxazolidinone derivatives were synthesized (Figure 4) and evaluated their substituted effects on in vitro and in vivo antibacterial activities activity against clinically relevant resistant gram-positive organisms, M. catarrhlis and H. influenzae with a long half-life.

Abstract

Some pentafluoropyridine derivatives have been synthesized by the reaction of pentafluoropyridine with appropriate C, S and N-nucleophile such as malononitrile, 1-methyl-tetrazole-5-thiol and piperazine. These reactions provided 4-substituted 2,3,5,6-tetrafluoropyridine derivatives in good yields. All the compounds were characterized using 1H, 13C and 19F-NMR spectroscopy and X-ray crystallography.

Keywords: Pentafluoropyridine, Heterocycle, Nucleophilic Substitution, Synthesis, 19F-NMR

Background

Pentafluoropyridine and related compounds in which all the hydrogen atom in heterocyclic ring have been replaced by fluorine atoms were synthesized by reaction of potassium fluoride with perchloro heteroaromatic (Ojima 2009). In pharmacology, it is common to substitute hydrogen with fluorine atoms for increases the lipophilicity and biological activity of the compounds (Chambers et al. 2008a, b). Pentafluoropyridine one of the most important perfluoroheteroaromatic compounds have been used for the synthesis of various drug-like systems (Gutov et al. 2010). These systems are highly active towards nucleophilic additions owing to the presence of electronegative fluorine atoms and the presence of the nitrogen heteroatom so all five fluorine atoms in pentafluoropyridine may be substituted by an appropriate nucleophile (Cartwright et al. 2010; Chambers et al. 2005). A nucleophilic substitution reaction of pentafluoropyridine occurs in two-step addition–elimination mechanism, so install nucleophile addition and in the end elimination flour ring nitrogen (Colgin et al. 2012). The site reactivity order of pentafluoropyridine is well known that, the order of activation toward nucleophilic attack follows these quence 4 (Para)-fluorine > 2 (Ortho)-fluorine > 3 (Meta)-fluorine so the reactions of pentafluoropyridine with some nucleophilic occur selectively at the Para position as this site is most activated towards nucleophilic additions to afforded of 4-substited tetrafluoropyridine (Chambers et al. 2008a, b).

Results and discussion

In this research, we describe nucleophilic substitution of pentafluoropyridine with a wide range of nucleophiles and highlight how the resulting products 4-substited-2,3,5,6-tetrafluoro-pyridine derivatives. Reaction of pentafluoropyridine 1 with malononitrile 2a under basic conditions (K2CO3) in DMF at reflux gave a 4-(malononitrile)-2,3,5,6-tetrafluoropyridine 6a (Fig. 1).

In basic condition, malononitrile 2a deprotonate and carbon nucleophile of malononitrile attack to Para position of pentafluoropyridine 1 and elimination of 4-fluor ring pyridine to give 5a. In 5a, hydrogen malononitrile very acidy so essay deprotonate in base solution to give potassium dicyano (perfluoropyridin-4-yl)methanide 6a (Fig. 2). Purification of 6a was achieved by recrystallization in ethanol/acetonitrile. In crystal 6a, two molecule chelate by potassium ion between flour and nitrogen. Identification of chelate 6a was done by 19F-NMR analysis, in which the resonance attributed to fluorines located Ortho to ring nitrogen has a chemical shift of -83.5 ppm and -84.4 ppm. The corresponding resonance for fluorines located Meta to ring nitrogen in chelate 6a occurred at −135.4 and −139.4 ppm. Four resonances by 19F-NMR indicate displacement of fluorine atoms attached to the Para position of two pyridine ring. The 1H-NMR spectra of compound 6a consisted of a H broad signal at δ = 7.29 ppm for CH malononitrile. X-ray crystallography confirmed the structure of chelate 6a (Figs. 3, ​4). A summary of the crystal data, experimental details and refinement results for 6a is given in Table 1.

Fig. 2

The suggested mechanism nucleophilic substitution of pentafluoropyridine with malononitrile

Reaction of 1-methyl-tetrazole-5-thiol 2b with pentafluoropyridine 1 in acetonitrile at reflux temperature and recrystallisation in ethanol gave 2-ethoxy-3,5,6-trifluoro-4-((1-methyl-1H-tetrazol-5-yl)thio)pyridine 5b (Fig. 5). In 1-methyl-1H-tetrazole-5-thiol, sulfur atom more nucleophilic than other atoms, so install attack at the Para position of the pyridine ring to give 4b. Purification of 4b was achieved by recrystallization in ethanol (accessible and non-toxic solvent). In hot EtOH, Ethoxy group attack at ortho position of 2,3,5,6-tetrafluoro-4-(1-methyl-1H-tetrazol-5-ylthio)pyridine 4b to give 5b (Fig. 6). Identification of 5b was done from 19F-NMR analysis in which the resonance attributed to displacement of fluorine atoms attached only at the Para and Ortho position of the pyridine ring. The corresponding resonance for F-3,5 (Meta) in 5b occurs at -131 and -154 ppm and F-6 (ortho) at −88 ppm. Other spectroscopic techniques were consistent with the structures proposed. The protons of the methyl group, were observed at δ = 4.13 ppm. The molecular structure of the 2-ethoxy-3,5,6-trifluoro-4-((1-methyl-1H-tetrazol-5-yl)thio) pyridine obtained has been determined by X-ray crystallography (Figs. 7, ​8). A summary of the crystal data, experimental details and refinement results for 5b is given in Table 1.

Fig. 5

Reaction of pentafluoropyridine with 1-methyl-tetrazole-5-thiol

Fig. 6

The suggested mechanism nucleophilic substitution of pentafluoropyridine with 1-methyl-1H-tetrazole-5-thiol

Also, we examined the reaction of pentafluoropyridine 1 with piperazine 2c in the presence of sodium carbonate in CH3CN solvent gave 1,4-bis(perfluoropyridin-4-yl)piperazine 3c (Fig. 9). In basic condition, two nitrogen of the piperazine deprotonation and attack to Para position of pentafluoropyridine and elimination of 4-fluor pyridine ring to give 3e (Fig. 10). Purification of 3c was achieved by recrystallization in acetonitrile. The structure of compounds 3c was confirmed by X-ray crystallography and by NMR spectroscopic data. In particular, 19F-NMR spectroscopy shows the chemical shift of fluorine atoms attached to the Ortho and Meta position are observed respectively at −97.3 and −160.5 ppm. In 1H-NMR, the protons of CH2 piperazine, was observed at δ = 4.3 ppm. The 13C-NMR spectrum of compound 3c showed 4 distinct resonances in agreement with the proposed structure. The structure of 3c was confirmed by X-ray crystallography (Figs. 11, ​12).

Fig. 10

The suggested mechanism nucleophilic substitution of piperazine with pentafluoropyridine

Conclusion

In conclusion, we showed that pentafluoropyridine can successfully react with a variety of nucleophiles to afford of 4-substited tetrafluoropyridine. The regioselectivity of nucleophilic substitution in this process may be explained by high nucleophilicity of sulfur, nitrogen or oxygen and activating influence of pyridine ring nitrogen that significantly activate the Para and Ortho sites to itself.

Experimental

All materials and solvents were purchased from Merck and Aldrich and were used without any additional purification. The melting points of the products were determined in open capillary tubes using BAMSTEAB Electrothermal apparatus model 9002. The 1H NMR spectra were recorded at 300 MHz. The 13C-NMR spectra were recorded at 75 MHz. The 19F-NMR spectra were recorded at 282 MHz. In the 19F-NMR spectra, up field shifts were quoted as negative and referenced to CFCl3. Mass spectra were taken by a Micro mass Platform II: EI mode (70 eV). Silica plates (Merck) were used for TLC analysis.

Preparation of 2-(perfluoropyridin-4-yl)malononitrile 6a

Pentafluoropyridine 1 (0.1 g, 0.6 mmol), malononitrile 2a (0.04 g, 0.6 mmol) and potassium carbonate (0.11 g, 1.0 mmol) were stirred together in DMF (5 mL) at reflux temperature for 3 h. The reaction mixture was evaporated to dryness than the solid product was recrystallisation from acetonitrile to give 2-(perfluoropyridin-4-yl)malononitrile (0.22 g, 86 %) as a red crystals; mp 260 °C dec, 19F NMR (acetone): 1H NMR (acetone): δ (ppm) 7.79 (s, 1H, CH); δ (ppm) −83.5 (m, 2F, F-2,6), −84.4 (m, 2F, F-2′,6′), −135.4 (m, 2F, F-3,5), −139.4 (m, 2F, F-3′,5′). MS (EI), m/z (%) = 508 (M+), 440, 364, 291, 180, 147, 121, 105, 91, 77, 57, 43.

Preparation of 2-ethoxy-3,5,6-trifluoro-4-((1-methyl-1H-tetrazol-5-yl)thio)pyridine 5b

Pentafluoropyridine 1 (0.1 g, 0.6 mmol), 1-methyl-1H-tetrazole-5-thiol 2b (0.09 g, 0.6 mmol) and sodium hydrogencarbonate (0.11 g, 1.0 mmol) were stirred together in CH3CN (5 mL) at reflux temperature for 4 h (monitored by TLC). The solvent was evaporated; water (5 mL) was added and extracted with dichloromethane and ethyl acetate (3 × 5 mL). Solvent evaporation and recrystallisation from ethanol gave 2-ethoxy-3,5,6-trifluoro-4-((1-methyl-1H-tetrazol-5-yl)thio)pyridine 5b (0.2 g, 75 %) as a white crystal; mp 130 °C dec. 1H NMR (acetone): δ (ppm) 1.37 (3H, m, CH3), 3.90 (3H, s, N-CH3), 4.3 (2H, m, CH2); 19F NMR (acetone): δ (ppm) −88.6 (1F, m, F-2), −131.4 (1F, m, F-3), −154.8 (1F, m, F-5); 13C NMR (acetone): δ (ppm) 14.6, 35.5, 63.2, 64.4, 139.2, 140.5, 142.6, 143.7, 145.9 ppm. MS (EI), m/z (%) = 292 (M+), 263, 235, 219, 180, 132, 100, 83, 43.

Preparation of 1,4-bis(perfluoropyridin-4-yl)piperazine 3c

Pentafluoropyridine 1 (0.1 g, 0.6 mmol), piperazine 2c (0.03 g, 0.5 mmol) and sodium hydrogencarbonate (0.11 g, 1.0 mmol) were stirred together in CH3CN (5 mL) at reflux temperature for 5 h. After complicated reaction, the solvent was evaporated; water (5 mL) was added and extracted with dichloromethane and ethyl acetate (3 × 5 mL). Solvent evaporation and recrystallization from CH3CN gave 1,4-bis(perfluoropyridin-4-yl)piperazine 3c (0.2 g, 52 %) as a white crystal; mp 288 °C dec. 1H NMR (acetone): δ (ppm) 4.30 (8H, s, CH2); 19F NMR (acetone): δ (ppm) −97.3 (4F, m, F-2,6), −160.5 (4F, m, F-3,5). 13C-NMR (acetone): δ (ppm) 60.3, 123.7, 127.1, 131.3 ppm. MS (EI), m/z (%) = 384 (M+), 317, 292, 263, 235, 219, 180, 152, 132, 116, 100, 83, 63, 43.

Authors’ contributions

KB, RH and MTM were involved in the study design and manuscript preparation, data collection, data analysis and revisions. All authors read and approved the final manuscript.

Acknowledgements

The authors wish to thank Evan Sarina from University of California for the partial support of this work.

Competing interests

None declared under financial, general, and institutional competing interests. I wish to disclose a competing interest(s) such as those defined above or others that may be perceived to influence the results and discussion reported in this paper.

Contributor Information

Khalil Beyki, Email: ri.ca.bsu.sgp@lilahkmehc.

Reza Haydari, Email: ri.ca.bsu.mehc@iradyeh.

Malek Taher Maghsoodlou, Email: ri.ca.bsu.mehc@uoldooshgam_tm.

References

  • Cartwright MW, Parks EL, Pattison G, Slater R, Sandford G, Wilson I, Yufit DS, Howard JAK, Christopher JA, Miller DD. Tetrahedron. 2010;66:3222–3227. doi: 10.1016/j.tet.2010.02.083.[Cross Ref]
  • Chambers RD, Khalil A, Murray CB, Sandford G, Batsanov AS, Howard JAK. J Fluor Chem. 2005;126:1002–1008. doi: 10.1016/j.jfluchem.2005.01.018.[Cross Ref]
  • Chambers RD, Martin PA, Sandford G, Williams DLH. J Fluor Chem. 2008;129:998–1002. doi: 10.1016/j.jfluchem.2008.04.009.[Cross Ref]
  • Chambers RD, Martin PA, Sandford G, Williams DLH. J Fluor Chem. 2008;129:998–1004. doi: 10.1016/j.jfluchem.2008.04.009.[Cross Ref]
  • Colgin N, Tatum NJ, Pohl E, Cobb S, Sandford G. J Fluor Chem. 2012;133:33–37. doi: 10.1016/j.jfluchem.2011.09.013.[Cross Ref]
  • Gutov AV, Rusanov EB, Ryabitskii AB, Chernega AN. J Fluor Chem. 2010;131:278–281. doi: 10.1016/j.jfluchem.2009.11.022.[Cross Ref]
  • Ojima I. Fluorine in medicinal chemistry and chemical biology. London: Blackwell; 2009.

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