The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• , respectively. Thakur and co-worker implemented the use of a nitrogen-rich tetrazole-linked ether group for a similar 1,2-trans stereodirecting property [160]. In this respect, they introduced the use of (1N/2N)-methylated tetrazole methyl (MeTetMe) ethers as a C-2 protecting group for glycosyl donors which was

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• transformation produced either the (Ra,Sa)-isomer using pyrrolidine tetrazole catalyst C6 or the (Sa,Sa)-diastereoisomer using quaternary ammonium salt C5 (Scheme 5). Catalyst-controlled formation of twofold and higher-order stereogenicity in axially chiral arenes was discussed in this account article [15

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• improved biological activities. Employing this approach, Kushwaha et al. [34] synthesized a series of compounds containing benzofuran, tetrazole, and pyrazole within a single structure (Scheme 2). Benzofurans and tetrazole pharmacophores have demonstrated potential anti-Alzheimer activity by inhibiting

• -Ugi transformations, it is possible to obtain diverse heterocyclic compounds with tetrazole moieties [65]. In this context, Medda et al. [66] developed a three-step process to access biologically active imidazotetrazolodiazepinones. The first one is the AU-4CRs among ethyl glyoxalate, amines

• of best derivatives obtained by Hasaninejad et al. [49]. Best DRD2 compounds synthesized using a multicomponent strategy. Oxoindole-β-lactam core produced in a U4C-3CR. Ugi-azide synthesis of benzofuran, pyrazole and tetrazole hybrids. Four-component Ugi reaction for the synthesis of novel

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• , 98160, México 10.3762/bjoc.20.256 Abstract A series of 1,5-disubstituted tetrazole-indole hybrids were synthesized via a high-order multicomponent reaction consisting of an Ugi-azide/Pd/Cu-catalyzed hetero-annulation cascade sequence. This operationally simple one-pot protocol allowed high bond-forming

• described (Scheme 1a–c). In 2021, Dömling’s research group synthesized a series of 1,5-disubstituted tetrazole-indoles 6 in good to excellent yields via an Ugi-azide/acidic ring-closure sequence [20]. Balalaie described an efficient method in 2018 for the synthesis of a new 1,5-disubstituted tetrazole

• -indole system 10, in a two-step reaction: Ugi-azide followed by a cyclization reaction catalyzed by AuCl3, in good to high yields [21]. In 2019, Salahi et al. synthesized the series of tetrazole-indoles 15 via an Ugi-azide reaction in moderate to high yields [22]. It is noteworthy that none of the

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• the reaction efficiency and selectivity was explored. A high selectivity was found for electron-withdrawing moieties, resulting in high yields of the N2-substituted products. Also, tetrazole 50 was arylated using the same hypervalent iodonium salts as a follow-up, but less than 14% of the targeted

• , reductive elimination of intermediate C yields the desired sulfoxides 87 (Scheme 36). Recently, a detailed study by Thakur and group on the metal-free arylation of tetrazole-5-thiols 88, exploring various substrate scopes under optimized conditions was conducted (Scheme 37) [90]. The findings indicated a

5th International Symposium on Synthesis and Catalysis (ISySyCat2023)

• Anthony J. Burke and
• Elisabete P. Carreiro

Beilstein J. Org. Chem. 2024, 20, 2704–2707, doi:10.3762/bjoc.20.227

• preparation of biologically active compounds [15]. The synthesis was achieved via a sulfonyl group rearrangement driven by the azide–tetrazole equilibrium in quinazolines. The researchers utilized two synthetic pathways to prepare the target compounds. The first pathway involved a nucleophilic aromatic

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• of an isocyanide, carbonyl, amine and TMSN3 to give tetrazole containing products. Isolated yields for eight analogs are reported with excellent retention of the deuterium label (Scheme 5). Of note, 3i was prepared from combination of a [D2]-isocyanide and a [D1]-aldehyde. Another versatile IMCR is

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• -ring bioisostere, but as carboxylic acid one, Schwarz et al. [79] developed tetrazole-based pregabalin bioisosteres 113–118 (Scheme 18). The target protein α2-δ is involved in neurotransmitters release reduction, as a model of anxiety and neuropathic pain. In general, submicromolar affinities were

• observed for this family of tetrazole scaffolds. Conclusion The present review focuses on an examination of the expanded 2-phenethylamine chemical space, highlighting heteroaromatic structures with reported pharmacological profiles. The close inspection of each of the phenyl and other heteroaryl ring

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• proved to be effective in a model oxidation reaction of n-octanol (2). Since previous investigations have repeatedly shown that the number of heteroatoms in the N-heterocycle correlates with the NHIs activity, a series of tetrazole- and tetrazine-substituted NHIs 1a–e was synthesized (Figure 2) [29][30

• : 3.61 Å [31]). Beginning with the electron-deficient and thereby highly reactive NHIs 1a and 1c, we explored the potential for a ligand-exchange process on the iodane via 1H NMR spectroscopy by combining equimolar quantities of NHI and n-octanol (2). When the tetrazole-substituted hydroxy(aryl)iodane 1a

• oxidation of the alcohol. Only small amounts of benzoic acid 4a’ were observed in all reactions with additional AlCl3, suggesting that the additive inhibits the previously observed overoxidation. Surprisingly AlCl3 activated the cyclic tetrazole iodane 1a but had almost no influence on the reactivity of the

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• Institute, Palackӯ University in Olomouc, Olomouc, Czech Republic 10.3762/bjoc.20.85 Abstract Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are

• introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent

• reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• Chemistry and Center for Green Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA 10.3762/bjoc.20.81 Abstract A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide

• and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE). Keywords: Heck reaction; one-pot; tetrahydroisoquinoline; tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones; tetrazole; Ugi-azide reaction

• ; Introduction Tetrazole is a privileged heterocycle existing in a range of biological and medicinally interesting compounds [1][2] with antifungal [3][4], antibacterial [5], anticancer [6][7], antiparasitic [8], and antihypertensive properties [9] including FDA approved drugs such as valsartan and cefmetazole

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl

• reaction of azoles with alkynes and iodine(III) electrophile, benziodoxole triflate (BXT, 1; Scheme 1c). Displaying exclusive trans-selectivity, the reaction tolerates a broad range of azoles, including pyrazole, 1,2,3-triazole, tetrazole, indazole, and benzotriazole, with internal alkynes as coupling

• , respectively. Tetrazole and 5-methyltetrazole both proved to be excellent substrates. Regardless of the presence or absence of the 5-substituent, they underwent preferential alkenylation at the N1 position over the N2 position with the identical regioselectivity of 7:3 (see 4ja and 4ka). Among other five

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• activity, if not an improvement [1]. Often-used bioisosteres include the tetrazole group for a carboxylic acid [2][3][4][5] and fluorine atoms in place of hydrogens [6][7]. The inclusion of fluorine can alter the polarity of a molecule and can also be used to prevent epimerisation, as seen in

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• -tetrazole, which was successfully used in many asymmetric reactions via “enamine activation”, especially in asymmetric aldol reactions [20][21][22][23]. Moreover, compound IV was previously included in a study dealing with asymmetric cascade reactions (based on aldol reactions) of aldehydes with α-keto

• -tolualdehyde afforded the aldol product only with a moderate yield of 30%; however, the diastereo- and enantioselectivity was satisfactory. A similar result was obtained in the reaction of 4-nitrobenzaldehyde with acetone. The comparison of IV with 5-(S)-pyrrolidin-2-yl-1H-tetrazole shows that both proline

• derivatives possess similar enantioselectivity. However, compound IV is less catalytically active, probably due to the lower acidity of protonated 1H-imidazole than 1H-tetrazole [17]. Conclusion In this study, we successfully synthesised enantiomerically pure stereoisomers of 2,2'-(pyridin-2,6-diyl)-bis

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• –tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core

• : aromatic nucleophilic substitution; azide–tetrazole equilibrium; 4-azido-2-sulfonylquinazolines; quinazolines; sulfonyl group dance; Introduction The quinazoline core is a privileged structure with a wide range of applications. Quinazoline derivatives exhibit a broad spectrum of biological activities

• azide–tetrazole equilibrium of product 12a was initiated, revealing a singular form present in all solvents. Despite attempts to increase the amount of the azide form with the increase of the temperature in NMR experiments [27], no observable alteration in the tautomeric equilibrium was observed. FTIR

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• ]. The ratio of α/β-anomers in compound 5 was found to be influenced by the reaction conditions, consistently favoring the β-anomer. Further transformation of compound 5 involved α-selective phosphite formation using dibenzyl N,N-diisopropylphosphoramidite and 5-(ethylthio)-1H-tetrazole. The resulting α

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• pyrazole derivatives (including indazole), benzimidazole, 1,2,3-triazole, indole, carbazole, indoline, quinazoline, and isoquinoline. Nevertheless, many heterocyclic motifs still remain beyond the attention of researchers. For example, glutarimides that incorporate tetrazole and 1,2,4-triazole substituents

Selectivity control towards CO versus H₂ for photo-driven CO₂ reduction with a novel Co(II) catalyst

• Lisa-Lou Gracia,
• Philip Henkel,
• Olaf Fuhr and
• Claudia Bizzarri

Beilstein J. Org. Chem. 2023, 19, 1766–1775, doi:10.3762/bjoc.19.129

• (NCS)2(NN) complexes, where NN is a chelating diimine compound such as pyridyl-tetrazole [44], or a pyridine-oxazole [45]. The bond lengths are very similar when comparing the polymorphs 1a and 1b. Nevertheless, the bond angles vary significantly (see Table S2 in Supporting Information File 1

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• 1H-tetrazole to produce the trialkyl phosphite 8.3 that was oxidized with tert-butyl hydroperoxide to produce phosphate 8.4. Then, β-elimination of the cyanoethyl protecting group produced PAF with a global yield of 70%. The limit of this method arises from the instability of the precursor 8.1 for

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• carbonyl group deactivation. Furthermore, while implementing the protocol for 2-azidoquinoline-3-carbaldehyde (1t), a low conversion of this reagent was detected, which can be explained by the fact that 1t tends to exist in the inactive tetrazole form. In addition, our attempt to involve Boc-protected

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• ; tetrazole; triazole; Introduction Quinoxalines are amongst the most versatile N-heterocyclic compounds, combining a straightforward synthesis with a diverse set of possible functionalizations and a wide range of applications in drug development and materials sciences [1]. Different quinoxaline derivatives

• ). Condensation to the corresponding quinoxalinone and subsequent chlorination was followed by introduction of the tetrazole moiety into the molecule via sodium azide to yield 11a–e. Alternatively, 4-chlorotetrazolo[1,5-a]quinoxaline (11f) was obtained after reaction of 2,3-dichloroquinoxaline (10f) with

• ). Increasing the amount of alkyne 4 increases the probability of the alkyne being coordinated in contrast to the tetrazole, which leads to launching of the CuAAC cycle. The probability of coordination on the tetrazole should also be indirectly impacted by this. However, the imidazole formation is only slightly

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• oxathiolane propionate derivative 43 by using Mucor miehei lipase, which affords (−)-enantiomer 44 as residual substrate. This enantioenriched precursor was useful to obtain the pure corresponding nucleoside analogue. Faury and co-workers [50] synthesized the tetrazole analogues of 1,3-oxathiolane nucleosides

• '-thiacytidine derivatives. The tetrazole analogues of 1,3-oxathiolane nucleosides were synthesized by Faury et al. [50]. N-Glycosylation of silylated tetrazole with 1,3-oxathiolane precursor 45 in the presence of titanium tetrachloride or TMSOTf, followed by deprotection in methanolic ammonia gave the final

• nucleoside 97 (Scheme 42). Unfortunately, the introduction of a tetrazole ring to the oxathiolane moiety did not result in any anti-HIV activity and higher cytotoxicity. The synthesis of N4-substituted analogue 99 of 2',3'-dideoxy-3'-thiacytosine was discovered by Camplo et al. (Scheme 43) [77]. The prodrug

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• different ketone and enone precursors from cholic acid, deoxycholic acid, and chenodeoxycholic acid was established. Newly obtained tetrazole derivatives were characterized by NMR and X-ray diffraction spectroscopy. In a number of cases, preliminary antiproliferative tests of new compounds showed strong and

• bile acids, derivatives with altered hydrophobicity are being studied [12][13][14]. The tetrazole moiety can be found in many biologically active compounds, and monosubstituted tetrazole is being used in medicinal chemistry as a bioisostere of carboxylic acid [15] because it increases the lipophilicity

• ]. The main approach in the synthesis of the tetrazoles is 1,3-dipolar cycloaddition between azide and nitrile. These reactions often follow the principles of “click” chemistry [20]. Although the formation of tetrazole in the Schmidt reaction of ketones was noted in the original study by Schmidt himself

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• mannuronic acid building blocks, appropriately modified at the carboxylate C6 position with a bioisosteric tetrazole. Thioglycosides containing a protected C6-tetrazole are accessed from a C6-nitrile, through dipolar cycloaddition using NaN3 with n-Bu2SnO. We also demonstrate access to orthogonally C4

• -protected donors, suitable for iterative oligosaccharide synthesis. The development of these building blocks is showcased to access anomeric 3-aminopropyl- and 1-phosphate free sugars containing this non-native motif. Keywords: alginate; glycosyl 1-phosphate; non-native monosaccharide; tetrazole; uronate

• , tetrazole (Figure 1b). As an established bioisostere for a carboxylic acid, tetrazole has found significant application within medicinal chemistry [12]. The aromatic tetrazole ring is considered a non-classical bioisostere, differing in size and number of atoms to the carboxylic acid. The functional group