Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling

• John M. Halford-McGuff,
• Thomas M. Richardson,
• Aidan P. McKay,
• Frederik Peschke,
• Glenn A. Burley and
• Allan J. B. Watson

Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265

• 10.3762/bjoc.20.265 Abstract We report the synthesis of germanyl triazoles formed via a copper-catalysed azide–alkyne cycloaddition (CuAAC) of germanyl alkynes. The reaction is often high yielding, functional group tolerant, and compatible with complex molecules. The installation of the Ge moiety enables

• azide precursors and the formation of a single 1,4-disubstituted triazole product, the copper-catalysed azide–alkyne cycloaddition (CuAAC) remains the archetypal click reaction (Scheme 1) [5]. The reaction has shown applicability on small and large scale, as well as under flow conditions [6], and

• converted to a mechanistically-required Cu(I) species in situ through the addition of a reductant (e.g., sodium ascorbate, NaAsc) [31][32], or via Glaser–Hay alkyne homocoupling [33][34]. The mild and accessible nature of the CuAAC reaction has allowed the use of azide or alkyne components that bear

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• , into the O–H bonds of diacid 6a (Scheme 5). Apparently, in this case, the reaction proceeds through a less sterically congested transition state. Diacyl chloride 2a was also reacted with sodium azide as nucleophile at room temperature giving dicarbonyl azide 12 in 85% yield (Scheme 6). Conclusion Two

• -2,2-dicarboxylic acids 6. Transformations of 3-(tert-butyl)-5-chloroisoxazole-4-carbonyl chloride (1j). Synthesis of amides 10. aFiltration through celite after reaction with amine (without aqueous workup). bWork up with H2O. Synthesis of esters 11. Synthesis of dicarbonyl azide 12. Synthesis of 5

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

• AChE, while pyrazole scaffolds possess the ability to reduce the tau and β-amyloid dual aggregation. Benzofuran-pyrazole aldehydes were employed in the Ugi azide reaction to give the desired hybrids. From the screened compounds, 2a, 2b, 2c, 2d, 2e, and 2f demonstrated notable efficacy in regulating the

• as nitro or azide groups, rather than protected amines. Following the Ugi-4CR, the nitro or azide group is reduced to form the amine, leading to a condensation reaction that results in the formation of the benzodiazepine ring [55]. Pertejo et al. [61] described the diastereselective synthesis of 3

• -carboxamide-1,4-benzodiazepin-5-ones when enantiopure (S)-(−)-α-methylbenzylamine and arylglyoxals were used. Thus, a reversal of diastereoselectivity was observed depending on the cyclization methodology employed, the reduction of a nitro group or the Staudinger/aza-Wittig on azide derivatives. This

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

• ; isocyanides; MCF-7 cell line; methanesulfonylindoles; Ugi-azide reaction; Introduction Nitrogen-containing heterocyclic moieties, such as 1,5-disubstituted tetrazoles and indoles, are considered pharmacophoric fragments due to their pivotal interactions with several targets involved in many diseases. They

• affinity compared to their drug parents and by using powerful synthetic tools such as multicomponent reactions (MCRs) [11][12][13]. Among these, isocyanide-based multicomponent reactions (I-MCRs), such as the Ugi-azide reaction, have demonstrated the highest biological-synthetic relevance [1][14][15][16

Tailored charge-neutral self-assembled L₂Zn₂ container for taming oxalate

• David Ocklenburg and
• David Van Craen

Beilstein J. Org. Chem. 2024, 20, 3007–3015, doi:10.3762/bjoc.20.250

• preparation and host assembly. The synthesis adheres to a two-synthon approach which relies on the connection of two building blocks through a CuAAC click reaction (Scheme 1). Building block S1, the azide, is not modified in this work and the preparation is achieved with an overall yield of 43% via the

• experiments (500 MHz, 500 µM, DMSO-d6, 25 °C) with mixtures of studied analytes showing the selective formation of the 1:1 oxalate host–guest complex [(C2)@L2Zn2]2− in all cases. Two-synthon approach for ligand preparation via CuAAC click reaction of an azide-functionalized, protected 8-hydroxyquinoline and a

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• authors reported Mn(II)-catalyzed azidation–peroxidation of alkenes 184 with TMSN3 and TBHP (Scheme 58) [127]. The proposed mechanism involves the formation of azide radical A and tert-butoxy radical B during the Mn(II)/Mn(III) redox catalytic cycle. Then, radical A adds to the double bond of the alkene

Synthesis of pyrrole-fused dibenzoxazepine/dibenzothiazepine/triazolobenzodiazepine derivatives via isocyanide-based multicomponent reactions

• Marzieh Norouzi,
• Mohammad Taghi Nazeri,
• Ahmad Shaabani and
• Behrouz Notash

Beilstein J. Org. Chem. 2024, 20, 2870–2882, doi:10.3762/bjoc.20.241

• organic azide that is very sensitive to external factors such as light, heat, friction, and pressure and should be stored in amber plastic containers without light and at a temperature below zero degree Celsius. Exposure to azide occurs through skin absorption, inhalation, or ingestion through the

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• application of the Mukaiyama redox condensation using N-iodosuccinic imide (NIS) afforded 10b. Hydrogenation resulted in defunctionalization to give 10c. Transformation of OH-4 to a triflate and subsequent reaction with sodium azide afforded gluco-configured product 10d. The latter was transformed to

• -glycoside 11a (Scheme 7) [20]. Debenzylation gave product 11b which was transformed to akashin A (11c) by reduction of the azide to the amine in the presence of propane-1,3-dithiol and subsequent debenzoylation. Akashin A was transformed to akashins B and C by acetylation and reaction with diacetyl

Investigation of a bimetallic terbium(III)/copper(II) chemosensor for the detection of aqueous hydrogen sulfide

• Parvathy Mini,
• Michael R. Grace,
• Genevieve H. Dennison and
• Kellie L. Tuck

Beilstein J. Org. Chem. 2024, 20, 2818–2826, doi:10.3762/bjoc.20.237

• proposed to function by Cu2+ sequestration. The remaining report is of a terbium(III) complex [Tb(DPA-N3)3]3− (Figure 7), which contains an aryl azide-functionalized ligand. In this system the azide functionality prohibits the energy transfer to the lanthanide ion, effectively quenching luminescence. In

• the presence of gaseous hydrogen sulfide, the aryl azide is reduced to an aniline functionality and luminescence is restored [11]. Drawing our previous findings and insights from the work of Hou, Wu, and co-workers [21], we postulate that gaseous H2S is interacting with the [Tb.1·3Cu]3+ complex as it

C–C Coupling in sterically demanding porphyrin environments

• Liam Cribbin,
• Brendan Twamley,
• Nicolae Buga,
• John E. O’ Brien,
• Raphael Bühler,
• Roland A. Fischer and
• Mathias O. Senge

Beilstein J. Org. Chem. 2024, 20, 2784–2798, doi:10.3762/bjoc.20.234

• examples are azide-porphyrin derivatives reported by Flanagan et al. [43]. Here, five crystal structures were obtained of meso-para-phenyl arm-extended porphyrins (26, 27, 28, 29, 33) and two crystal structures for meso-meta-phenyl derivatives 36 and 37. In addition, single crystal structures of 11 and 46

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

• in MeOH at room temperature with a short reaction time. Some of them were further functionalized with a 1,2,3-triazole ring via copper-catalyzed azide–alkyne cycloaddition (CuAAC) and deprotected with trifluoroacetic acid. Several hybrids were evaluated against six cancer cell lines, displaying GI50

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• functionalized pyrimido[5,4-b]indoles due to its high functional group tolerance. Multiple examples were demonstrated with indole 1H-carboxamides linked to drug molecules or natural products at the R2 position. Additionally, an alkyl azide at the R2 position and an iodide at the R1 position were tolerated

• this method (Scheme 30b). 1.3 Metal-assisted anodic oxidation 1.3.1 Mn-assisted anodic oxidation. The Ackermann group was the first to achieve an C–H azidation by use of a manganese-catalyzed anionic oxidation using “traceless electrons” [42]. By employing inexpensive sodium azide and a manganese salen

• undergoes hydrogen-atom transfer (HAT) leading to alkyl radical formation. The manganese-catalyzed azide radical transfer then delivers the product. Unactivated secondary and tertiary C–H bonds, as well as benzylic C–H bonds, were prone to azidation, with the reactivity order being: benzylic > tertiary

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• prerequisite required for a probe used in a chemical proteomic study is an embedded bioorthogonal handle, for example a terminal alkyne or azide, which is able to react chemoselectively with a tag facilitating unambiguous identification by a selected analytical technique, for example LC–MS/MS (Figure 1) [35

• bearing an affinity or reporter tag. To carry out this bioorthogonal reaction well-known chemistries were developed including traceless Staudinger ligation, Cu-catalyzed azide–alkyne cycloaddition (CuAAC), strain-promoted azide–alkyne cycloaddition (SPAAC), inverse electron-demand Diels–Alder reaction

• –protein conjugates are reacted via CuAAC with an azide tag. While the CuAAC has been employed in various studies and has had large impact on many biological discoveries, an unspecific reactivity was often reported [54][64]. Recently, we described this background-forming reaction, which is based on an

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

• been demonstrated to work without loss of deuterium in the Ugi-3CR. First reported in 1961, the Ugi-azide reaction differs from the classical Ugi 4-CR in that an azide anion traps out the intermediate nitrilium ion, leading to formation of α-aminotetrazoles [36][37][38][39]. Thus, it comprises reaction

• . No deuterium scrambling observed. Ugi-azide reaction products, no deuterium scrambling observed. Passerini products, no deuterium scrambling observed. aWater was used as solvent. Strecker reaction products (precursors to [D1]-α-amino acids), no deuterium scrambling was observed. aThe cyano-group was

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• Naoki Takeda Shuichi Akasaka Susumu Kawauchi Tsuyoshi Michinobu Department of Materials Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552, Japan 10.3762/bjoc.20.191 Abstract Strain-promoted azide–alkyne cycloaddition (SpAAC) is a powerful tool in

• azide–alkyne cycloaddition; Introduction The strain-promoted azide–alkyne cycloaddition (SpAAC) is one of the most representative metal-free click chemistry reactions [1][2][3][4][5]. SpAAC has been mainly employed in bioconjugation in the fields of chemical biology and medicinal chemistry due to its

• ], and crosslinked polymers [14][15][16][17]. Since crosslinking polymers requires high reaction efficiency under mild conditions, developing such reactions is crucial. We previously reported the regioselective double azide addition to octadehydrodibenzo[12]annulene with hexyloxy substituents (DBA-OHex

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• to 97%. The Sonogashira coupling can also be effectively integrated with the CuAAC (copper-catalyzed azide–alkyne cycloaddition) reaction, offering a powerful tool for synthesizing diverse molecular architectures. In a consecutive multicomponent reaction, pyrazoles were first presented in a

• and cesium azide for the synthesis of compounds 120. The choice of the hydrazine substituent represents a limitation, as no aromatic substituents are tolerated in the strategy due to the reduced reactivity. However, due to the building blocks’ simplicity, various 4-pyrazolyl-1,2,3-triazoles are

• cycloaddition, the corresponding pyrazoles are formed by elimination of the azide group and subsequent tautomerization. Thus, the process enables access to 3,5- and 3,4,5-substituted pyrazoles 171 and also allows the synthesis of pyrazole 3-carboxylates (Scheme 57) [174]. An alternative method for the

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• closure to furnish the 1,2,4-triazolium 97 (Scheme 18) [65]. In the last example of this section, only one nitrogen atom of the hydrazone takes part in the cycloaddition reaction. In 2018, Zhang et al. realized the electrochemical (3 + 2)-cycloaddition of trimethylsilyl azide (102) with aldehyde-derived N

• ,N-disubstituted hydazones 101 for synthesiszing tetrazoles 103. Sodium azide could be an alternative source of azide, albeit with both slightly lower yields and Faradic efficiency. Remarkably, (hetero)aromatic as well as aliphatic aldehydes proved to be efficient. Various substituents on the N(sp3

• ) atom were well tolerated and the best result was obtained with a morpholine ring. Based on cyclic voltammetry studies, the transformation initiated with the anodic oxidation of hydrazone 101 to form highly electrophilic radical cationic species 104. Subsequent addition of azide 102 and desilylation

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

• comprising a GBB-3CR and a palladium-catalyzed azide-isocyanide coupling to generate imidazo[1,2-a]pyridine-fused 1,3-benzodiazepines 85 (Scheme 27). The GBB reaction smoothly proceeded using 2-azidobenzaldehydes 83, 2-aminopyridines and isocyanides as the precursors. The in situ-generated azides 84 were

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• methodology has several drawbacks, as the need to synthesise the 2-azidobenzoic acid from anthranilic acid and sodium azide, the requirement of anhydrous conditions to perform the Staudinger/aza-Wittig sequence or the generation of large quantities of triphenylphosphine oxide which needs to be removed by

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• diazo precursor. To achieve this, cholesterol was first esterificated using 2-(4-methoxyphenyl)acetic acid and DCC. The resulting arylacetic ester 12 was then reacted with 4-acetamidobenzenesulfonyl azide (p-ABSA) and DBU in anhydrous acetonitrile to yield the diazo compound 13 in 22% yield. The carbene

• epoxide was then opened by treatment with sodium azide and boric acid, yielding the azide derivative 146 in 87% from estrone. A subsequent reduction of the azide with LiAlH4 provided the aminoalcohol derivative 147 in 64% yield. Then, a chloroacetamido moiety was formed at the amino function in 51% yield

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• reaction with biotin azide, which led to selective pull-down with streptavidin agarose and isolation of the probe–protein covalent complex. Proteomic analysis of the isolated proteins narrowed down the MaMO and MaDA candidates, including several berberine bridge enzyme (BBE)-like enzymes. This FAD-linked

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• an ammonium hypoiodite species which first facilitates the α-iodination of the pronucleophile, followed by a phase-transfer-catalyzed nucleophilic substitution by the azide. Furthermore, we also show that an analogous α-nitration by using NaNO2 under otherwise identical conditions is possible as well

• . Keywords: azidation; nitration; organocatalysis; oxidation; quaternary ammonium iodides; Introduction Organic compounds containing an azide functionality are highly valuable synthesis targets that offer considerable potential for various applications and further manipulations [1][2][3][4][5][6][7][8][9

• consequence, the synthesis of organic azides is an important task and it comes as no surprise that a variety of conceptually complementary strategies to install azide groups in organic molecules have been reported [1][2][3][4][5][6][7][8]. α-Azido carbonyl derivatives are especially interesting targets which

Synthesis of cyclic β-1,6-oligosaccharides from glucosamine monomers by electrochemical polyglycosylation

• Md Azadur Rahman,
• Hirofumi Endo,
• Takashi Yamamoto,
• Shoma Okushiba,
• Norihiko Sasaki and
• Toshiki Nokami

Beilstein J. Org. Chem. 2024, 20, 1421–1427, doi:10.3762/bjoc.20.124

• formation of larger cyclic oligosaccharides. Electrochemical polyglycosylation of 2-azido-2-deoxy-substituted thioglycoside monomers Based on the results shown in Table 1 and Scheme 3, we changed the substituent in position C-2 of the thioglycoside monomer from PhthN to azide, which has no neighboring group

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• the triazole unit via a copper-catalyzed azide–alkyne cycloaddition. The developed methodology was used to synthesize a library of over fifty new multi-substituted pyrazole–triazole hybrids. We also demonstrate a one-pot strategy that renders the isolation of potentially hazardous azides obsolete. In

• addition, the compatibility of the method with solid-phase synthesis is shown exemplarily. Keywords: azide; click reaction; CuAAC; pyrazole; triazene; triazole; Introduction Nitrogen-containing heterocycles are central scaffolds in medicinal chemistry and are incorporated in most small-molecule drugs [1

• cholerae [13], show antimicrobial properties [14], and can act as P2X7 antagonists, a receptor involved in neuroinflammation and depression [15]. Pyrazolyltriazoles are most easily obtained via the copper-catalyzed azide–alkyne cycloaddition (CuAAC) from pyrazolyl azides (7 and 8). These are usually

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• and Figure 2). Like the oxindole scaffold, 1,2,3-triazole is also considered a privileged unit in drug discovery since compounds having this structure have a broad spectrum of biological activities, and have been widely used to create anticancer drug candidates [24][25]. The copper-catalyzed azide

• into the scaffold. Benzyl azide (6), obtained using a previously reported procedure [27], was used in the CuAAC reaction. The α-acetamide carboxamide 1,2,3-triazole oxindole hybrid 7 was easily obtained in 61% yield using Cu(OAc)2 as catalyst, ascorbic acid, DMF as solvent, and microwave reaction