Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• rhodium(III)-catalyzed intermolecular annulation has been established for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacetylenes to form the hybrid products in moderate to very good yields. The method relies on the capacity of the

• rhodium catalyst to promote C(sp2)–H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diversity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal center. The scope of the

• . Keywords: C–H activation; cyclization; isoquinolone; multicomponent reaction; tetrazole; Introduction Pyridones and isoquinolones are relevant heterocyclic scaffolds present in numerous bioactive compounds and natural products [1][2][3][4]. Similarly, molecules containing a tetrazole ring exhibit a wide

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• -withdrawing properties of the tetrazole ring, which makes them useful for studying various theoretical issues, e.g., tautomerism [5], intramolecular transformations [6], etc. There are several approaches to the synthesis of 4,7-dihydrotetrazolo[1,5-a]pyrimidines. Two of them make use of 5-aminotetrazole as a

• accessible by variation of the binucleophilic component 1 (instead of 1, 3-amino-1,2,4-triazole, 2-aminobenzimidazole, 3-aminopyrazoles, 4-amino-1,2,3-triazoles, etc. can be used [13]). However, a relatively low reactivity of amine 1 due to the electron deficiency of the tetrazole ring has been reported

• several times [5][6]. A third approach (Scheme 1, reaction 3) is completely different and consists of the tetrazole ring formation through cyclization of dihydropyrimidinethiones with sodium azide [14]. Generally, all three approaches allow for the preparation of a broad range of compounds 3 with a wide

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• -(ethylthio)-1H-tetrazole as activator instead of the typically used acetic anhydride. Oxidation was performed under standard conditions. The last nucleotide at the 5'-end of ODN was incorporated with a 5'-trityl nucleoside phosphoramidite instead of a 5'-DMTr counterpart. At the end of the synthesis, the 5

• × 2; coupling, phosphoramidite (0.1 M, MeCN), 5-(ethylthio)-1H-tetrazole (0.25 M, MeCN), 60 s × 3 (or 2); capping, 25 (0.1 M, MeCN) and 5-(ethylthio)-1H-tetrazole (0.25 M, MeCN), 60 s × 3; oxidation, I2 (0.02 M, THF/pyridine/H2O, 70/20/10, v/v/v), 40 s. For incorporating the last nucleoside monomer, a

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• of polystyrene resin 3 as the amine component. After resin removal with piperidine in DMF, a combinatorial strategy of replacing the carboxylic acid component with trimethylsilyl azide (TMSN3) (azido-Ugi reaction) or cyanic acid, followed by Fmoc removal (TFA), allowed the formation of the tetrazole

• tetrazole-ketopiperazines (Scheme 3). The strategy involved three steps: first, an Ugi tetrazole reaction between isocyanoacetate derivatives 8, tritylamine (9), various aldehydes and TMSN3, followed by treatment of the products with aqueous HCl, which cleaved both the trityl group and the methyl ester, to

• yield amino acids 11 bearing a 1,5-disubstituted tetrazole. The practicality of the Ugi tetrazole reaction (also called Ugi-azide or azido-Ugi reaction) has been recently reviewed [20][21]. These compounds were then used in an intramolecular three-component four-center Ugi reaction using equimolar

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• equilibrium was studied in different deuterated solvents by 1H NMR spectroscopy on the example of 6-azido-9-heptyl-2-piperidinopurine 6b. Experiments were performed in CDCl3, THF-d8, CD3CN and DMSO-d6. The 1H NMR spectrum in CD3CN showed the presence of the tetrazole form and has been used for NMR studies in

• stability [39]. Regarding the tautomerism in 2,6-diazido-substituted starting materials, it has been studied previously for both purine [41] and 7-deazapurine [52] derivatives. In both cases practically only the diazido forms are observed in chloroform solution, but the proportion of the tetrazole tautomer

• wavelengths at 420 nm (Semrock, Rochester, NY, USA). Examples of fluorescent purine/7-deazapurine derivatives. 1H NMR spectra of compound 6b in CD3CN at different temperatures (300 MHz, c = 12.5 mg/mL); a, b, c – signals for azide form 6b-A; α, β, γ – signals for tetrazole form 6b-T). Comparison of 1H NMR

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• -transfer difference NMR (STD-NMR) led to the identification of thirty fragments. Subsequent 2D-15N–1H HSQC NMR returned four fragment hits 28–31 (Figure 7), with binding affinities, determined by NMR titration, in the low millimolar range. Of all of the fragments, tetrazole 31 was chosen for further

• optimization due to its physicochemical properties and its potential for fragment growth. After virtual screening and binding studies by STD-NMR studies, the authors were able to find tetrazole 32 (Figure 7) which had a three-fold improved affinity (Kd = 1.3 mM) compared to the initial hit 31. Later, the ZINC

• database [82] was searched for structurally similar compounds leading to the identification of the meta-substituted tetrazole 33 (Figure 7), which was found to have a similar dissociation constant. Moreover, in order to predict the orientation of the fragments in the binding site, molecular docking of 33

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• ]. The supported trinucleotide 1 was prepared from the support in 83% yield over 8 steps (Scheme S1, Supporting Information File 1) and used as a model in combination with 5-(benzylmercapto)-1H-tetrazole (BMT) as an activator (Table 1). The reaction was found to be rather sensitive to the concentration

• , entry 4). When the activator was switched to tetrazole, the yield was slightly decreased (Table 1, entry 5), while dicyanoimidazole (DCI) was proven to be an inefficient option for the reaction (Table 1, entry 6). It should be noted that the 5’-activated supported trinucleotide 2 was stable throughout

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• free NH group possess a low enough pKa to allow Mitsunobu coupling. In the course of the synthesis of the hexasaccharidic fragment of landomycin A, the L-rhodinose derivative 121 underwent glycosylation with 1H-tetrazole to give 122, which has a pKa that compares to carboxylic acids (Scheme 24) [89

• iminoglycosylphthalimide 115 from 114 [85]. Mitsunobu reaction as a key step in the total synthesis of aurantoside G [87]. Utilization of an N–H acid in the Mitsunobu reaction [88]. Mitsunobu reaction with 1H-tetrazole [89]. Formation of a rebeccamycin analogue using the Mitsunobu reaction [101]. Synthesis of

Recent advances in phosphorescent platinum complexes for organic light-emitting diodes

• Cristina Cebrián and
• Matteo Mauro

Beilstein J. Org. Chem. 2018, 14, 1459–1481, doi:10.3762/bjoc.14.124

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

• Katharina Hiebler,
• Georg J. Lichtenegger,
• Manuel C. Maier,
• Eun Sung Park,
• Renie Gonzales-Groom,
• Bernard P. Binks and
• Heidrun Gruber-Woelfler

Beilstein J. Org. Chem. 2018, 14, 648–658, doi:10.3762/bjoc.14.52

• donating as well as electron withdrawing functional groups, as coupling partners (Scheme 1). Concerning the targeted synthesis of 1, aryl halide 4e was of special interest as the cyano group is known to be convertible to the ortho-tetrazole moiety [9] present in the API. Based on prior optimisation studies

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• agents and readily undergoes β-elimination [27]. An alternative reagent is 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphordiamidite in combination with tetrazole derivatives such as benzylmercaptotetrazole. Under those conditions, the phosphitylation proceeds with the production of one equivalent of

• diisopropylamine, which is neutralized by benzylmercaptotetrazole released back after the reaction. The tetrazole derivative is sufficiently acidic to act as a scavenger for diisopropylamine converting it into the ammonium salt. Thus, fully protected trimers can be converted to phosphoramidites without the loss of

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• -diethylaminophosphepane (N,N-diethyl-1,5-dihydro-2,3,4-benzodioxaphosphepin-3-amine) in the presence of 1H-tetrazole followed by in situ oxidation with m-chloroperoxybenzoic acid (m-CPBA) to give fully protected 4’-phosphate 2. The azido group in 2 was reduced, the resulting amine was converted to the N-Fmoc carbamate

• in AcOH which reductively cleaved the N-Troc group (Scheme 3). After N-acylation by (R)-3 acyloxyacyl fatty acid and hydrolytic cleavage of 4’,6’-O-benzylidene acetal group with 90% aqueous TFA, the liberated 6’-hydroxy group was regioselectively protected as TBDMS ether to furnish 20. 1H-Tetrazole

• deprotection by catalytic hydrogenation furnished lipid A 31. Alternatively, the lactol 30 was phosphitylated by application of the phosphoramidite procedure with (benzyloxy)[(N-Cbz-3-aminopropyl)oxy](N,N-diisopropylamino)phosphine in the presence of 1H-tetrazole and subsequent oxidation with dimethyldioxirane

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• ); Ugi-azide reaction; Introduction Tetrazoles are extensively studied, useful non-natural heterocyclic skeletons with the highest nitrogen content among the stable heterocycles [1][2]. The tetrazole-ring system has a variety of applications in organic chemistry, coordination chemistry, and agriculture

• and, in particular, it displays a wide range of biological properties such as analgesic, anti-inflammatory, antiviral, anticancer, among others [3][4][5]. The tetrazole nucleus most widely described in the literature is the 1,5-disubstituted tetrazole [6][7] because it presents a wide range of

• pharmacological activities. For instance, cilostazol (anti-inflammatory), pentylenetetrazol (circulatory and respiratory stimulant) and nojiritetrazole (antidiabetic) are drugs containing the 1,5-disubstituted tetrazole nucleus, along with the pharmaceutically important tetrazoles losartan and valsartan, which

¹⁵N-Labelling and structure determination of adamantylated azolo-azines in solution

• Sergey L. Deev,
• Alexander S. Paramonov,
• Tatyana S. Shestakova,
• Igor A. Khalymbadzha,
• Oleg N. Chupakhin,
• Julia O. Subbotina,
• Oleg S. Eltsov,
• Pavel A. Slepukhin,
• Vladimir L. Rusinov,
• Alexander S. Arseniev and
• Zakhar O. Shenkarev

Beilstein J. Org. Chem. 2017, 13, 2535–2548, doi:10.3762/bjoc.13.250

• product structure were also found for N-arylation or N-alkylation with tert-butyl fragments in the series of 1,2,3-triazole [15][16], tetrazole [17][18][19][20], and purine [21] derivatives. Meanwhile, knowledge of the accurate chemical structures of N-substituted heterocycles is essential for biomedical

• give [1,2-15N2]-tetrazolo[5,1-c][1,2,4]triazine 11-15N2. Indeed, [2,3-15N2]-tetrazolo[1,5-b][1,2,4]triazin-7-one 13-15N2 was obtained (see below). Most likely, tetrazole 11-15N2 underwent a ring-opening process, yielding azide 12-15N2, and this process was followed by an alternative ring closure. This

• azido-tetrazole equilibrium has been previously studied in detail [25]. The coupling between compound 13-15N2 and 1-adamantanol (14) was conducted in trifluoroacetic acid (TFA) solution under reflux. A general and convenient approach to the N-adamantylation of heterocycles involves a reaction with the

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• (R in the 4-position of the ring), which was attributed to an equilibrium of azide–tetrazole. In the solid state, all compounds were found as 2-azidopyrimidines. The regiochemistry of the reaction and the stability of the products are discussed on the basis of the data obtained by density functional

• theory (DFT) for energetic and molecular orbital (MO) calculations. Keywords: 5-aminotetrazol; azide–tetrazole equilibrium; 2-azidopyrimidine; β-enaminones; tetrazolo[1,5-a]pyrimidine; trifluoromethylatedtetrazolo[1,5-a]pyrimidines; Introduction Tetrazolo[1,5-a]pyrimidines have attracted attention in

• 1960s and 1970s reported the existence of an azide–tetrazole equilibrium in many heterocyclic systems, namely tetrazolopyridines, tetrazolopyridazines, tetrazolopyrimidines, tetrazoloazines, and tetrazolopurines. Both tetrazole and azide have different chemical properties. Among other factors, the

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• the nucleobases are usually protected with acyl groups and the 5´-OH of the monomeric building block with a 4,4’-dimethoxytrityl group (DMTr), or sometimes with its monomethoxytrityl analog (MMTr) [4][5]. To achieve coupling, phosphoramidites are activated with azoles [6], such as tetrazole [7], its

• the early 1980s, according to which appropriately protected nucleosides could rapidly be coupled as 3´-(O-alkyl-N,N-dialkylphosphoramidite)s to 5´-OH of a support bound nucleoside by using tetrazole as an activator [7]. Since then, this solid-supported phosphoramidite chemistry has almost exclusively

• hydroperoxide in MeCN [52]. On using 2.5 equiv of the phosphoramidite block and 10 equiv of tetrazole as an activator in MeCN, 98–99% coupling yields were obtained. Support-bound octamer, DMTr-d(5´-TAGCGCTA-3´)-PEG could be obtained in 93% yield and a 20-mer in 85% yield. These yields are surprisingly high

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

• Ilya V. Efimov,
• Marsel Z. Shafikov,
• Nikolai A. Beliaev,
• Natalia N. Volkova,
• Tetyana V. Beryozkina,
• Wim Dehaen,
• Zhijin Fan,
• Viktoria V. Grishko,
• Gert Lubec,
• Pavel A. Slepukhin and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2016, 12, 2390–2401, doi:10.3762/bjoc.12.233

• in the literature in comparison with monocyclic and fused derivatives [1][6]. Recently isoxazoles conjugated to pyrazole A [12], imidazole B [13] and tetrazole C [4] rings were found as promising candidates for anticancer and antidiabetic drugs and for the treatment of cognitive disorder (Figure 1

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• good enantioselectivities and diastereoselectivies (Scheme 19) [35]. The tetrazole unit and the secondary amide of the catalyst in cat. 6 were the key moieties for the good stereoselectivity. However, the reactions required long reaction times (up to 6 days). This protocol was then successfully applied

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• aureus), VRE and Hi (Haemophilus influenzae) bacterial strains, it is currently undergoing clinical trials. An earlier docking study of 7 by Shaw et al. [47] postulated an increased potency mediated by additional interactions between the ribosomal active site and the pyridine and tetrazole rings from 7

Synthesis of cyclic N¹-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

• Ahmed Mahal,
• Stefano D’Errico,
• Nicola Borbone,
• Brunella Pinto,
• Agnese Secondo,
• Valeria Costantino,
• Valentina Tedeschi,
• Giorgia Oliviero,
• Vincenzo Piccialli and
• Gennaro Piccialli

Beilstein J. Org. Chem. 2015, 11, 2689–2695, doi:10.3762/bjoc.11.289

• regioisomer 7 equipped with the reactive phosphorous(III) group. Unfortunately, the activation of the phosphoramidite function with 1H-tetrazole aimed at inducing the cyclization on the 5’-OH ribose function produced only a complex mixture. No traces of the target cyclic compound were detected after the usual

• -tetrazole, THF, 2) t-BuOOH, 2 h, rt; iii) 1) (iPr)2NP(OCE)2, 1H-tetrazole, THF, 2 h, rt, 2) t-BuOOH, 2 h, rt; iv) TEA/pyridine, 1:1 v/v, 16 h, rt; v) activating agent (EDC in DMF or DCC in DMF or MSNT in pyridine) 16 h, rt; vi) conc. aq NH4OH, MeOH, 50 °C, 16 h. i) DNCB, K2CO3, DMF, 4 h, 80 °C; ii) 5

• -aminopentan-1-ol, DMF, 16 h, 50 °C; iii) Ac2O, pyridine, 2 h, rt, iv) NH4F, MeOH, 16 h, reflux; v) 1) (iPr)2NP(OCE)2, 1H-tetrazole, THF, 2 h, rt, 2) t-BuOOH, 2 h, rt; vi) conc. NH4OH(aq), MeOH, 50 °C, 16 h; vii) EDC, DMF; viii) TFA, H2O, 16 h, rt. Supporting Information Supporting Information File 542

Syntheses of 2-substituted 1-amino-4-bromoanthraquinones (bromaminic acid analogues) – precursors for dyes and drugs

• Enas M. Malik,
• Younis Baqi and
• Christa E. Müller

Beilstein J. Org. Chem. 2015, 11, 2326–2333, doi:10.3762/bjoc.11.253

• -tetrazolylanthraquinone (11). The conversion was completed within 8 min as determined by TLC, but surprisingly no trace of the desired tetrazole 11 was detected by LC–MS. We presume that the tetrazole was unstable under the applied reaction conditions [66]. Tetrazole derivative 11 was alternatively obtained in excellent

• yield and purity by refluxing nitrile 12 with sodium azide and ammonium chloride in DMF, followed by treatment with bromine to yield the corresponding brominated tetrazole 10 in excellent yield and high purity (see Scheme 3, Table 1). The same strategy (bromination in the last step) was subsequently

• access to tetrazole 10 in high yield and purity, but also conversion of the hydroxymethyl group of compound 5 to cyano, carbaldehyde, and carboxylate groups yielding compounds 12, 13, and 14, required shorter reaction times, and provided somewhat higher overall yields as compared to the corresponding

The reactions of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole as a way to novel azaheterocycles

• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess and
• Viktor I. Saloutin

Beilstein J. Org. Chem. 2015, 11, 385–391, doi:10.3762/bjoc.11.44

• ways of cyclization. Such changes may be caused by lower basicity of 5-AT (pKb = 12.18 [21]) compared with other aminoazoles and the ability of its derivatives to azide–tetrazole isomerism [22][23]. The present paper focuses on studying the peculiarities of interaction of 2-ethoxymethylidene-3-oxo

• tetrazolylaminomethylidene derivative B. As a result of regiospecific addition of NH-group to acyl fragment, the intermediate B gives dihydrotetrazolo[1,5-a]pyrimidine C, which is further transformed into tetrazolo[1,5-a]pyrimidine D after elimination of water. Because of the ability of tetrazole to ring opening at the N1

• –N8 bond, tetrazolo[1,5-a]pyrimidine D undergoes azide–tetrazole isomerism to form isomeric 2-azidopyrimidines 2a–c. The electron-withdrawing substituents in the heterocycle are known to facilitate the opening of the fused tetrazole ring because of decreased electron density at the bridgehead nitrogen