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

Unusual behavior in the reactivity of 5-substituted-1H-tetrazoles in a resistively heated microreactor

• Bernhard Gutmann,
• Toma N. Glasnov,
• Tahseen Razzaq,
• Walter Goessler,
• Dominique M. Roberge and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2011, 7, 503–517, doi:10.3762/bjoc.7.59

• Chemistry, Karl-Franzens-University Graz, Universitätsplatz 1, A-8010 Graz, Austria Continuous Flow/Microreactor Technologies, Lonza AG, CH-3930 Visp, Switzerland 10.3762/bjoc.7.59 Abstract The decomposition of 5-benzhydryl-1H-tetrazole in an N-methyl-2-pyrrolidone/acetic acid/water mixture was

• investigated under a variety of high-temperature reaction conditions. Employing a sealed Pyrex glass vial and batch microwave conditions at 240 °C, the tetrazole is comparatively stable and complete decomposition to diphenylmethane requires more than 8 h. Similar kinetic data were obtained in conductively

• heated flow devices with either stainless steel or Hastelloy coils in the same temperature region. In contrast, in a flow instrument that utilizes direct electric resistance heating of the reactor coil, tetrazole decomposition was dramatically accelerated with rate constants increased by two orders of

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• suffer from poor absorption and low bioavailability. At this stage a classical bioisostere exchange, i.e., replacing a carboxylic acid group with a tetrazole ring, was performed which resulted in increased lipophilicity [48] and the development of the orally active losartan. In the absence of a crystal

• and dichloromethane selectively provides tertiary alcohol 183. In subsequent steps this imidazole is alkylated with the tetrazole containing biphenyl appendage, followed by ester hydrolysis and alkylation of the resulting carboxylate with 4-(chloromethyl)-5-methyl-2-oxo-1,3-dioxole to yield olmesartan

• regioselectivity of the imidazole formation. The benzimidazole ring is then assembled by treating this diamine with tetraethyl orthocarbonate under Lewis acid conditions. The synthesis is concluded by installation of the tetrazole ring and acetal side chain, the latter is cleaved under physiological conditions

RAFT polymers for protein recognition

• Alan F. Tominey,
• Julia Liese,
• Sun Wei,
• Klaus Kowski,
• Thomas Schrader and
• Arno Kraft

Beilstein J. Org. Chem. 2010, 6, No. 66, doi:10.3762/bjoc.6.66

• slope of the binding curve. Graphical illustration of the potential binding mode on hemoglobin tetramer (represented as electrostatic potential surface, lysines = blue). The RAFT copolymer T20CH15 (tetrazole rings = red) undergoes an extensive induced fit procedure on the protein surface maximizing

A short and efficient synthesis of valsartan via a Negishi reaction

• Samir Ghosh,
• A. Sanjeev Kumar and
• G. N. Mehta

Beilstein J. Org. Chem. 2010, 6, No. 27, doi:10.3762/bjoc.6.27

• -tetrazole (6) and its Negishi coupling with aryl bromide 5 are the key steps of the synthesis. This method overcomes many of the drawbacks associated with previously reported syntheses. Keywords: antihypertensive therapy; aryl bromide; Negishi coupling; tetrazole; valsartan; Introduction Valsartan (Figure

• important goal. In this paper, we report a new, concise and efficient synthesis of valsartan via Negishi coupling. Results and Discussion From a retro-synthetic analysis (Scheme 1), compound 8 could be constructed via Negishi coupling from aryl bromide 5 and 5-phenyl-1-trityl-1H-tetrazole (6), which in turn

• -pentanoyl-L-valinate (5) [9] in 70% yield. Ortho-metalation of 5-phenyl-1-trityl-1H-tetrazole (6) [10] with n-butyllithium at 25 °C followed by treatment with zinc chloride at −20 °C gave the desired organozinc chloride compound. Coupling of the latter with aryl bromide 5 in presence of a catalytic amount

Synthetic incorporation of Nile Blue into DNA using 2′-deoxyriboside substitutes: Representative comparison of (R)- and (S)-aminopropanediol as an acyclic linker

• Daniel Lachmann,
• Sina Berndl,
• Otto S. Wolfbeis and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2010, 6, No. 13, doi:10.3762/bjoc.6.13

• modified with the acyclic linked acetylene was performed using a modified protocol. Activator solution (0.45 M tetrazole in acetonitrile) was pumped together with the building block (0.15 M in acetonitrile) through the CPG vial. The coupling time was extended to 61 min with an intervening step after 30.8

Asymmetric reactions in continuous flow

• Xiao Yin Mak,
• Paola Laurino and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19

• in the near future. Enantioselective addition of trimethylsilyl cyanide to benzaldehyde. Asymmetric catalytic hydrogenation in a falling-film microreactor. Aldol reaction catalyzed by 5-(pyrrolidine-2-yl)tetrazole. Enantioselective addition of diethylzinc to aryl aldehydes. Glyoxylate-ene reaction in