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

Synthesis of a bifunctional cytidine derivative and its conjugation to RNA for in vitro selection of a cytidine deaminase ribozyme

• Nico Rublack and
• Sabine Müller

Beilstein J. Org. Chem. 2014, 10, 1906–1913, doi:10.3762/bjoc.10.198

• , which was coupled with synthon 12 in anhydrous THF in the presence of 5-benzylmercapto-1H-tetrazole (BMT) as activator (Figure 5). The coupling product 16 was isolated with a yield of 28%. Finally, all remaining protecting groups were cleaved off. The base-labile β-cyanoethyl (CE) group was removed by

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• substrate afforded nucleosides 30 bearing a N-acyl α-amino acid amide moiety at the uracil C-5 carbon atom (Scheme 14) [79]. The variant of the reaction with trimethylsilyl azide (TMS-N3) in place of the carboxylic acid gave the tetrazole-substituted nucleosides 31 [79]. Products 30 and 31 were obtained as

• the reaction was performed with an excess (1.5 equiv) of methyl acetoacetate and methyl 3-aminocrotonate under L-proline-catalyzed conditions. In contrast to other catalysts tested (ytterbium triflate, D-proline, (S)-5-(pyrrolidin-2-yl)-1H-tetrazole, or (S)-1-(pyrrolidin-2-ylmethyl)pyrrolidine/TFA

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• ], the CB1 receptor of cannabinoid and fatty acid amide hydrolase [114][118][119][120][121]. In this context, Hulme and co-workers described a Passerini multicomponent approach towards cis-constrained norstatine mimics, a class of HIV-1 protease inhibitors with a tetrazole core (Scheme 45) [122]. They

• showed that a TMSN3-modified Passerini 3-CR gave easy access to tetrazole building blocks that, after N-Boc-deprotection, could be coupled with polymer-bound tetrafluorophenol-esters. Subsequent heating provided the desired N-coupled Norstatine peptidomimetics 149 (HPLC purities: 30–74%), in which

• -position and can be obtained for example from β-amino acids. During the Ugi reaction, the tetrazole moiety is obtained from a sigmatropic rearrangement (Scheme 47). Subsequent base-treatment enables β-elimination, which is driven by mesomeric stabilization of the triazole ring, resulting in the desired 5

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• alcohol cis-adamantane-2-spiro-3’-8’-hydroxymethyl-1’,2’,4’-trioxaspiro[4.5]decane 183. The latter was mesylated to 184 (cis-adamantane-2-spiro-3’-8’-methanesulfonylmethyl-1’,2’,4’-trioxa-spiro[4.5]decane), and used in the reaction with sodium 1-methyl-1H-tetrazole-5-thiolate 185 for the synthesis of cis

• -adamantane-2-spiro-3’-8’-[[(1’-methyl-1’H-tetrazol-5’-yl)thio]methyl]-1’,2’,4’-trioxaspiro[4.5]decane 186 through nucleophilic substitution of the mesyl group by the thio group of tetrazole 185 (Scheme 49) [297]. Ozonide 188 was synthesized by Mitsunobu reaction of alcohol 183 with pyridin-4-ol (187) (Scheme

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• corresponding acid chloride of oxadiazole derivative 3.23. This particular oxadiazole 3.23 was prepared via a clever sequence involving acylation of methyl tetrazole (3.24) with ethyl oxalylchloride (3.25) to form intermediate 3.26 which when heated extrudes nitrogen gas and subsequently collapses to the

Stereoselective synthesis of the C79–C97 fragment of symbiodinolide

• Hiroyoshi Takamura,
• Takayuki Fujiwara,
• Isao Kadota and
• Daisuke Uemura

Beilstein J. Org. Chem. 2013, 9, 1931–1935, doi:10.3762/bjoc.9.228

• (Scheme 4). The synthesis started from commercially available methyl (S)-3-hydroxy-2-methylpropanoate (21), which was converted to alcohol 22 by the known method [22]. Alcohol 22 was treated with 1-phenyl-1H-tetrazole-5-thiol/DEAD/PPh3 to furnish the corresponding PT-sulfide, which was oxidized with H2O2

Synthesis and quantitative structure–activity relationship study of substituted imidazophosphor ester based tetrazolo[1,5-b]pyridazines as antinociceptive/anti-inflammatory agents

• Wafaa M. Abdou,
• Neven A. Ganoub and
• Eman Sabry

Beilstein J. Org. Chem. 2013, 9, 1730–1736, doi:10.3762/bjoc.9.199

• . The anti-inflammatory and the antinociceptive properties of the prepared compounds were screened and the structure–activity relationships were studied. The anti-inflammatory properties of many tetrazole [21][22][23] and pyridazine derivatives have also led to their clinical application as NSAIDs (e.g

• been reported that 3,6-diazidopyridazine presents azido (1a) tetrazolo tautomerism (1b) whereby it is mainly in the tetrazole form 1b [27][28][29]. Accordingly, and as indicated from the spectral data of our products, we considered that the substrate 3,6-diazidopyridazine (1a) is exclusively

• the formation of tetrazolopyridazinophosphonate 4 is presented in Scheme 1. Upon heating, the equilibrium between the azido-1a and its isomeric tetrazolo-1b form [1a 1b] lies exclusively at the tetrazole isomer 1b [29]. Compound 1b is then intercepted by the nucleophilic attack of the phosphonyl

Camera-enabled techniques for organic synthesis

• Steven V. Ley,
• Richard J. Ingham,
• Matthew O’Brien and
• Duncan L. Browne

Beilstein J. Org. Chem. 2013, 9, 1051–1072, doi:10.3762/bjoc.9.118

• ]. The route required a significant quantity of an orthogonally protected piperazic acid (Figure 10). This was achieved using a new enantioselective organocatalytic protocol with a tetrazole organocatalyst, which afforded dihydro pyridazines from achiral aldehydes [61][62]. Unfortunately, while this

Methylidynetrisphosphonates: Promising C₁ building block for the design of phosphate mimetics

• Vadim D. Romanenko and
• Valery P. Kukhar

Beilstein J. Org. Chem. 2013, 9, 991–1001, doi:10.3762/bjoc.9.114

• tetraphosphate analogue 47 was obtained upon treatment of chloromethylidynetrisphosphonic acid 44 with excess AMP morpholidate. The incorporation of the third adenylate moiety was found to be extremely slow; however, the use of tetrazole as catalyst allowed the preparation of P1,P2,P3-tris(5'-adenylyl

• acid via trisphosphonate salt 38. Synthesis of halomethylidynetrisphosphonate salts 43 and 44 by modified Gross’s procedure. Synthesis of trisphosphonate modified nucleotides. Reagents: i, 5'-O-tosyl adenosine, MeCN; ii, AMP–morpholidate (0.8 equiv), tetrazole, pyridine; iii, AMP–morpholidate (5 equiv

• ), tetrazole, pyridine; iv, excess AMP–morpholidate, pyridine; v, AMP–morpholidate (2.2 equiv), tetrazole, pyridine. All counterions are tri-n-butylammonium. Ado = 5'-adenosyl. Ionisation constants for polyphosphonic acids determined in the range 3.5 < pH < 10.5 at 37 °C and 0.152 M NaCl [7]. Acknowledgements

4-Pyridylnitrene and 2-pyrazinylcarbene

• Curt Wentrup,
• Ales Reisinger and
• David Kvaskoff

Beilstein J. Org. Chem. 2013, 9, 754–760, doi:10.3762/bjoc.9.85

• phenylnitrene to 5-cyanocyclopentadiene has a calculated barrier of ca. 30 kcal/mol [15]. FVT of the tetrazole 23 at 400 °C/10−4 mbar causes loss of N2 and formation of 2-diazomethylpyrazine (22), which is easily observed directly by its strong absorption at 2080 cm−1 when the pyrolysate is isolated neat in

Spin state switching in iron coordination compounds

• Philipp Gütlich,
• Ana B. Gaspar and
• Yann Garcia

Beilstein J. Org. Chem. 2013, 9, 342–391, doi:10.3762/bjoc.9.39

• -tetrazole)6]X2 complexes, which are nearly regular octahedral [50]. Another possibility to fulfill the condition for thermal spin crossover to occur is the coordination of a hexadentate system, such as the mixed aliphatic/heterocyclic tetrakis(2-pyridylmethyl)ethylenediamine) [51] or the completely

• complexes of iron(II) with tetrazole and triazole ligands are generally weakly colored or nearly white in the HS state but purple in the LS state. If such ligand field transitions are well resolved and not hidden by more intense parity- and spin-allowed charge-transfer bands, the optical spectrum recorded

Diarylethene-modified nucleotides for switching optical properties in DNA

• Sebastian Barrois and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2012, 8, 905–914, doi:10.3762/bjoc.8.103

• research. Modified oligonucleotides were synthesized by a modified protocol. The activator solution (0.45 M tetrazole in MeCN) was pumped simultaneously with the building block 17 [30] and the coupling time was extended to 35 min, with an intervening step after 17.5 min for washing and refreshing of the

An easy α-glycosylation methodology for the synthesis and stereochemistry of mycoplasma α-glycolipid antigens

• Yoshihiro Nishida,
• Yuko Shingu,
• Yuan Mengfei,
• Kazuo Fukuda,
• Hirofumi Dohi,
• Sachie Matsuda and
• Kazuhiro Matsuda

Beilstein J. Org. Chem. 2012, 8, 629–639, doi:10.3762/bjoc.8.70

• phosphocholine group at the sugar 6-OH position, we employed a phosphoroamidite method using 1H-tetrazole as a promoter [34]. First, 8a was treated with 2-cyanoethyl-N,N,N’,N’-tetraisopropyl phosphorodiamidite in the presence of 1H-tetrazole, and then with choline tosylate to give 9a. After removal of the sugar

• phosphorodiamidite (90.4 mg, 0.30 mmol) in 10 mL of CH2Cl2 was injected. 1H-tetrazole (28.4 mg, 0.40 mmol) was added and stirred for 2 h at rt. Then 1H-tetrazole (42.6 mg, 0.60 mmol, 3.0 equiv) and choline tosylate (220.3 mg, 0.8 mmol: thoroughly dried overnight under vacuum) were added to the reaction mixture and

• . Syntheses of GGPL-I homologue I-a and its isomer I-b. Conditions: (a) K2CO3, CH3OH; (b) cesium palmitate in DMF; (c) TBDMS chloride then palmitoyl chloride in pyridine + DMAP; (d) TFA in CH3OH; (e) (i) 2-cyanoethyl-N,N,N’,N’-tetraisopropyl phosphorodiamidite, 1H-tetrazole and MS-4 Å in CH2Cl2; (ii) choline

Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

• Lucie Brulikova and
• Jan Hlavac

Beilstein J. Org. Chem. 2011, 7, 678–698, doi:10.3762/bjoc.7.80

• -methylmorpholine-N-oxide, acetone H2O t-BuOH (4:1:1), 15 h, 44%; (d) Ac2O, pyridine, 44 h, 96%; (e) TBAF, THF, 14 h, 75%; (f) DMTrCl, DMAP, Et3N, pyridine, 22 h, 78%; (g) [(iPr)2N]2POCH2CH2CN, tetrazole, 2.5 h, quant. Reaction conditions 2: (a) TBDMSCl, imidazole, DMF, over night; (b) 5 mol % Pd(MeCN)2Cl2, Bu3SnCH