A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• which could not be fully purified or characterised but has a characteristic AQ quartet of two protons replacing the singlet for the N-methyl group in the 1H NMR spectra consistent with a cyclometallated complex from C–H insertion [31][32]. Three distinct sets of N-methyl and N-methylsulfonyl signals

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• (namely furan-2(5H)-ones, tetrahydrofurans and pyrans spiro-conjugated with the succinimide ring) has been developed. The protocol consists of Rh(II)-catalyzed insertion of heterocyclic carbenes derived from diazoarylidene succinimides (DAS) into the O–H bond of propiolic/allenic acids or brominated

• alcohols, followed by base-promoted cyclization to afford the target spirocyclic compounds in good to high yields. Keywords: diazoarylidene succinimides; intramolecular cyclization; rhodium(II) carbene O–H insertion; spirocycles; Introduction Spirocyclic motifs have emerged as auspicious frameworks for

• synthesis of spiro-annulated pyrrolidine-2,5-diones by catalyzed spirocyclizations involving aldehydes [11], tetrahydrofuran [12][13], and in the O–H insertion/Claisen rearrangement/intramolecular oxa-Michael addition cascade [14] (Scheme 1). Herein, we report our findings obtained, while investigating the

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• synthesis and a final closure of the 7-membered ring by C–C bond formation. This is in sharp contrast with the widely adopted strategy relying on the late-stage insertion of the sulfur atom with concomitant ring closure, using either electrophilic or nucleophilic sulfur reagents. By way of example, thiepine

• corresponding bis(thiophenyl) thioether, which then underwent successive bromination and iodination to give intermediate 18. Next, a two-fold Suzuki–Miyaura cross-coupling occurring chemoselectively on the iodinated positions allowed the symmetric extension of the hydrocarbon scaffold, with the insertion of two

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• esters; Introduction The insertion of fluorine-containing components frequently confers desirable physical and biological properties to organic molecules, and the development of fluorine-containing drugs is an important field of research [1][2][3][4][5][6][7][8][9]. It is estimated that 30% of drugs and

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• (1a), followed by the oxygen-promoted insertion of the phenylboronic acid coupling partner 7 to deliver intermediate II that undergoes reductive elimination to give diarylamine 3a along with regeneration of the copper catalyst (Scheme 5). Then, a palladium-promoted oxidative addition of the C–Br bond

• takes places to deliver palladium species III. Then the insertion of CO that is released by Mo(CO)6, should afford intermediate IV that undergoes a base-promoted intramolecular cyclization via nucleophilic attack of the amine [31]. Finally, the dibenzodiazepinone 4a would be obtained through reductive

Long oligodeoxynucleotides: chemical synthesis, isolation via catching-by-polymerization, verification via sequencing, and gene expression demonstration

• Yipeng Yin,
• Reed Arneson,
• Alexander Apostle,
• Adikari M. D. N. Eriyagama,
• Komal Chillar,
• Emma Burke,
• Martina Jahfetson,
• Yinan Yuan and
• Shiyue Fang

Beilstein J. Org. Chem. 2023, 19, 1957–1965, doi:10.3762/bjoc.19.146

• 399 and 401 bp fragments from sequencing confirmed clones were elongated with PCR using appropriate primers (see Supporting Information File 1 for details) so that the fragments have homologous overlapping ends with each other and with the insertion sites of the vector. The PCR elongated ≈399 and ≈401

• some biological applications [30][31]. Besides quantity, for long ODN synthesis, the accuracy of the product is also important. According to reported data [26], common errors in synthetic ODNs include substitution, insertion, and deletion, and their rates are 0.045% (dG to dA 0.11%, dT to dC 0.01%, dC

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

• component into a glutarimide framework employing a Rh2(esp)2-catalyzed N–H insertion with the involvement of N-Boc-α-diazo glutarimide. The new diazo reagent is more stable, soluble and convenient to prepare than the previously suggested one. The approach permits the application of diverse heterocycles

• , including both aromatic and saturated NH-substrates. This yields structures that are appealing for generating cereblon ubiquitin-ligase ligands and for potential use in crafting PROTAC molecules. Keywords: CRBN ligands; diazocarbonyl compounds; N–H insertion reaction; N-heterocycles; Rh(II)-catalysis

• acknowledged to be effective in introducing substituents to the nitrogen atoms of NH-heterocycles by means of carbene insertion into the N–H bond upon catalytic or photolytic decomposition of diazo compounds [25]. Furthermore, the reaction of N-heterocycles containing multiple non-equivalent nitrogen atoms

Synthetic approach to 2-alkyl-4-quinolones and 2-alkyl-4-quinolone-3-carboxamides based on common β-keto amide precursors

• Yordanka Mollova-Sapundzhieva,
• Plamen Angelov,
• Danail Georgiev and
• Pavel Yanev

Beilstein J. Org. Chem. 2023, 19, 1804–1810, doi:10.3762/bjoc.19.132

• -mediated domino reaction of chromone-3-carboxaldehydes and amines [41], Pd-catalyzed redox-neutral C–N coupling reaction of iminoquinones with electron-deficient alkenes [42], NH3 insertion into o‑haloarylynones [43], gold(III)-catalyzed azide-yne cyclization [44], Michael/Truce-Smiles rearrangement

Recent advancements in iodide/phosphine-mediated photoredox radical reactions

• Tinglan Liu,
• Yu Zhou,
• Junhong Tang and
• Chengming Wang

Beilstein J. Org. Chem. 2023, 19, 1785–1803, doi:10.3762/bjoc.19.131

• and a PPh3–I radical III. The subsequent isocyanide 44 SOMOphilic insertion reaction led to the formation of an imidoyl radical B. This radical then underwent rapid addition onto the C–C double bond, resulting in the release of the desired phenanthridine products 45. Importantly, this process also

Synthesis of 7-azabicyclo[4.3.1]decane ring systems from tricarbonyl(tropone)iron via intramolecular Heck reactions

• Aaron H. Shoemaker,
• Elizabeth A. Foker,
• Elena P. Uttaro,
• Sarah K. Beitel and
• Daniel R. Griffith

Beilstein J. Org. Chem. 2023, 19, 1615–1619, doi:10.3762/bjoc.19.118

• cleanly according to TLC analysis, but the isolated yield of the intramolecular Heck product was low, perhaps due to instability of one of the intermediate palladium complexes and/or a slow olefin insertion step. Moreover, the product was obtained as an inseparable mixture of the allylic carbamate 18 and

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• of aryl sulfides by using the catalyst and the base. A catalytic cycle is shown in Scheme 4. Firstly, electrophilic Pd(TFA)2 generated from Pd(OAc)2 and TFA, which (by C–H functionalization of arene 4) led to intermediate II. Oxidative insertion of intermediate II into the N–S bond of 1 afforded

• in the presence of TEMPO, followed by insertion of an isocyanide molecule 166 or other nucleophiles 161 (Scheme 72) [102]. By studying the spectroscopic evidence, the authors found that both sulfenyl halide 165 and N-sulfenylsuccinimide 1 intermediates were involved in the reaction. Removal of TEMPO

Unravelling a trichloroacetic acid-catalyzed cascade access to benzo[f]chromeno[2,3-h]quinoxalinoporphyrins

• Chandra Sekhar Tekuri,
• Pargat Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2023, 19, 1216–1224, doi:10.3762/bjoc.19.89

• ) porphyrins were transformed to the corresponding free base and zinc(II) benzo[f]chromeno[2,3-h]quinoxalinoporphyrins under standard demetallation and zinc insertion conditions. The absorption and emission properties of the obtained porphyrins were investigated by using UV–visible and fluorescence

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• 44, from which reductive elimination of iodobenzene would generate 40. In 2021, Sen and Gremaud disclosed a blue LED-mediated formal C–H insertion reaction between iodonium ylides (e.g., 31) and pyrroles (e.g., 45), indoles and furans, producing malonate-substituted heterocycles 46 (Scheme 9) [126

• ]. The authors discounted a free carbene-based C–H insertion because conducting the reaction in the presence of the radical trap phenyl N-tert-butyl nitrone (PBN) and the radical scavenger TEMPO resulted in decreased yields and isolation of their iodonium ylide adducts. Additional kinetic isotope effect

• iodobenzene then generated a strained, cyclopropane-fused bicycle 49 that rearranged into the isolated C–H insertion product 46a. In addition to Neiland’s disclosure of the reactions between iodonium ylides and hydrochloric acid (Scheme 1) [1][102], others have also reported that both strong acids (e.g., TsOH

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• mechanism involves the coordination of pyridine to the metal center of the cationic catalyst and B(C6F5)3 promotes the ortho-C–H activation (deprotonation) of pyridine to afford pyridyl species 6. Next, the 2,1-migratory insertion of alkene 2 into the metal–pyridyl bond in 6 gives the intermediate 7, which

• on subsequent deprotonation gives the branched alkylated product 4. Whereas, in case of styrene 3 a 1,2-insertion takes place possibly due to the formation of the stable benzallylic species 8, which on deprotonation gives the linear alkylated product 5. The C–H activation/C–C cross-coupling reaction

• significantly affect the C–H alkylation reaction and the reaction also proceeded well with hydrazones 13 obtained from aliphatic aldehydes or ketones. Based on mechanistic experiments and DFT calculations, the reaction presumably proceeds via a Cu–carbene migratory insertion (Scheme 4b). In the presence of CuI

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• -Cl [21], 3,4-di-Cl [21][22], 2/3/4-F [23]) were inserted in the N-benzyl moiety as well as in the aromatic rings of the benzophenone fragment [24][25][26] (selected examples are given in Scheme 1). Insertion of halogen atoms increased enantioselectivity, e.g., in alkylation reactions [27][28

• including the thiolation discussed above). Insertion of the t-Bu group also makes the (GlyNi)L7 complex more soluble in diethyl ether as compared to the parent (GlyNi)L1 complex (21.3 mg/1 mL vs <1 mg/1 mL in Et2O; see Figure 3). This is beneficial for electrosynthesis, simplifying the separation of the

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• metal catalysts towards coordination on the exo face biases the reaction outcome towards exo-selective functionalization. Upon exo coordination of a metal catalyst with the π system and subsequent migratory insertion, the resulting alkyl metal intermediate is quite limited in how it can propagate. In

• on the functionalization of the bicyclic framework itself rather than its use as a transient mediator for domino reactions [13][14][15][16][17]; however, we point the reader to several excellent reviews. The “trapped” alkyl metal intermediate can undergo subsequent migratory insertion steps with

• exo coordination of a metal catalyst with the π system and migratory insertion, the resulting heterobicyclic alkyl metal intermediate is not as kinetically stable as its carbocyclic counterpart. While β-H elimination is still limited, these heterobicyclic alkenes will often undergo β-heteroatom

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• functionalisation of unsaturated bonds [1][2][3][4][5], and, more recently, frustrated Lewis pair (FLP) chemistries including small molecule activations and C–H insertion reactions [6][7][8][9][10]. Group 13 exchange is the transfer of one or more substituents from one group 13 element to another group 13 element

• /B‒H exchange [114]. Hevia reported a combination of a tris(alkyl)gallium species and bulky N-heterocyclic carbene acted as an FLP for B‒H insertion, and was used subsequently as a catalyst in the hydroboration of ketones, aldehydes, esters, and imines with HBpin [115]. Using an ONO-pincer-supported

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• pleuromutilin tricyclic scaffold construction. Alternative reagents were thus explored to close the eight-membered ring via initial radical genesis. For instance, Bacqué et al. reported the insertion in the cyclization precursors of functional groups prone to form radicals (Scheme 35). In their investigations

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• ; pyrazole carbaldehydes; sulfur insertion; thioamides; Introduction During the past years, the significance of pyrazole chemistry has been notably escalated which is attributed to the discovery of their amazing biological properties. Among the heterocyclic molecules, pyrazoles are considered as privileged

• 10A in high yields (67–71%) within 1 hour of reaction time as depicted in Scheme 3. Thereafter, the substrates 4-iodopyrazole-3-carbaldehydes were further investigated for this metal- and catalyst-free sulfur insertion reaction as shown in Scheme 4. It was found that 4-iodopyrazole C-3 carbaldehydes

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• activation/annulation cascade of readily available enaminones with iodonium ylides towards the convenient synthesis of isocoumarins. This coupling system proceeds in useful chemical yields (up to 93%) via a cascade C–H activation, Rh-carbenoid migratory insertion and acid-promoted intramolecular annulation

• , which undergoes a rapid migratory insertion to give intermediate 1-C. The protonation of 1-C produces the intermediate 1-D with the regeneration of the active Rh catalyst for the next catalytic cycle. Under acidic conditions, the further protonation of compound 1-D delivers an imine intermediate 1-E

Digyalipopeptide A, an antiparasitic cyclic peptide from the Ghanaian Bacillus sp. strain DE2B

• Adwoa P. Nartey,
• Aboagye K. Dofuor,
• Kofi B. A. Owusu,
• Anil S. Camas,
• Hai Deng,
• Marcel Jaspars and
• Kwaku Kyeremeh

Beilstein J. Org. Chem. 2022, 18, 1763–1771, doi:10.3762/bjoc.18.185

• insertion of different amino acids, homologous extension and linear, isopropyl or isobutyl termination of fatty acid chains. Therefore, the biosynthesis of compound 1 is speculated to occur via a similar pathway like the surfactins, which is known to be modulated by four enzyme subunits SrfAA, SrfAB, SrfAC

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• subdivided into groups of genes called syntenic blocks [82]. Among related strains, the order of these syntenic blocks, as well as their gene composition, is highly similar (Figure 7). Evolutionary young HGT events in single/few strains can disrupt this order, leading to the insertion of non-syntenic blocks

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• insertion of carbenes derived from diazo arylidene succinimides (DAS) into the O–H bond of phenols is described. The initial adducts underwent a thermally promoted Claisen rearrangement followed by DABCO-catalyzed intramolecular 5-exo-trig oxa-Michael addition. Keywords: Claisen rearrangement; diazo

• arylidene succinimides; intramolecular oxa-Michael addition; rhodium(II) carbene O–H insertion; spirocycles; Introduction Spirocycles undoubtedly occupy a special place in drug design [1] and, in general, spirocyclic compounds intended for the interrogation of biological targets have been associated with

• cyclohexanone (as well as other cyclic ketones) which delivered spiro-annulated 2-benzoxepines (such as 2a) along with a minor byproduct 3a identified by 1H NMR as the product of formal insertion of the rhodium(II) carbene species into the O–H bond of cyclohexanone enol form. This minor byproduct, on heating at

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• the 6-5-5 tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C–H insertion. Keywords: aberrarone; C–H insertion; gold; Pauson–Khand; total synthesis; Introduction Marine natural

• one quaternary carbon stereocenter and 1,2-dikeone moiety, Nazarov cyclization [33] of 7 was proposed for synthesizing this challenging moiety. The corresponding precursor cyclopentenone 8 may be prepared from alkynone 9 through a gold-catalyzed C–H insertion [34]. Alkynone 9 could be achieved through

• strategy, the stereogenic center at C1 was synthesized, along with a smooth attachment of the cyanate group served for further functional group transformation to construct the C ring through C–H insertion. The stereochemistry finding of this conjugate addition from the convex face of the 6-5 ring system

Mechanochemical bottom-up synthesis of phosphorus-linked, heptazine-based carbon nitrides using sodium phosphide

• Blaine G. Fiss,
• Georgia Douglas,
• Michael Ferguson,
• Jorge Becerra,
• Jesus Valdez,
• Trong-On Do,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2022, 18, 1203–1209, doi:10.3762/bjoc.18.125

• , examples of carbon nitride materials linked together via phosphorus atoms are limited, likely due to challenges in controlling the insertion of phosphorus atoms as linkers under high energy conditions. Mechanochemistry [9][10][11][12] has proven to be effective for the synthesis of a variety of polymers