Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• the alkene moiety of the amine. The resulting stabilized carbocation 15 is then captured by formaldehyde (generated in situ from DMSO) leading to an intermediate oxocarbenium 16 that undergoes a cyclization to obtain the sulfenylated oxazinane derivative 13. In isotope labelling experiments using DMSO

• of an N–C bond, where the stability of the leaving carbocation is the main factor that affects the rate of this step. Next, intermediate 37 is attacked by the phosphorus compound, giving product 35 with retention of the configuration. This mechanism was confirmed when compound 36a was isolated as

• product 35b was obtained, confirming that the dihaloalkane compound is the source of the methylene unit (Scheme 28c). Depending on the stability of the leaving carbocation, the selectivity of the R–N cleavage follows the decreasing order for the R groups: H, t-Bu, allyl, benzyl > methyl > primary

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

• the inversion at the anomeric sp3 carbon centre by the attack of the acceptor moiety. Crich β-mannosylations are classic illustrations for the same [38][39]. On the other hand, the stability of the carbocation contributes towards the reaction to proceed via the dissociative two-step SN1 reaction

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• the allyl carbenium ion VI through the loss of a molecule of water, then undergoes a Friedel–Crafts alkylation by attack of the aromatic partner. The outcome of the reaction proceeds through a Markovnikov protonation of the allylated arene VII by triflic acid, which generates the carbocation

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

• molecule of TBHP is oxidized by Fe(III) into tert-butylperoxy radical B. Radical A abstracts a hydrogen atom from ether 78 to give the C-centered radical C. The authors propose two further pathways for the formation of the target product 79. Pathway I: The C-centered radical C is oxidized to carbocation D

• ), abstracts hydrogen atom from silyl allene 122 to form the C-centered propargylic radical B. Fe(III) oxidizes radical B to carbocation C which reacts with Fe(III)OO-t-Bu complex D to yield the target peroxide 123. Cyclopropanols 124 [101] and their derivatives 128 [102] were used as a source of alkyl moiety

• final peroxide 157: recombination of radical C with tert-butylperoxy radical D or oxidation of radical C to carbocation E, which is nucleophilically attacked by TBHP. β-Peroxy ketones 159 were synthesized via oxidative dimerization of styrenes 158 using the Cu(I)/TBHP system (Scheme 50) [42]. The

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

• carbocation intermediate, which rearomatizes through proton loss. Concurrently, the cathodic reduction of the generated protons produces H2. In addition to (hetero)aromatic groups, alkene scaffolds also underwent this reaction (Scheme 3). In the same year, the Lei group [10] extended the electrochemical C(sp2

• . Mechanistically, this transformation can be understood as follows: first, a Br/Cl/CF3 radical is formed via anodic oxidation, which subsequently attacks the olefin. The newly formed benzyl radical is oxidized to a carbocation, which undergoes nucleophilic attack by DMF. Hydrolysis of the imine delivers the final

• oxidized to a carbocation, which is subsequently attacked by the alkoxide to furnish the final product (Scheme 17). The Lei group also demonstrated C–F-bond formations, particularly developing an electrochemical method for the cleavage of C–C bonds and the 1,3-difunctionalization of arylcyclopropanes [26

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• one diastereomer of 7q was formed (Scheme 4). This result is in accordance with the calculated mechanism. The more electron-rich trisubstituted alkene 3r reacted directly with Selectfluor leading to a tertiary carbocation which was trapped by acetonitrile in a Ritter-type process to generate bisamide

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

• Phong Thai,
• Lauv Patel,
• Diyasha Manna and
• David C. Powers

Beilstein J. Org. Chem. 2024, 20, 2305–2312, doi:10.3762/bjoc.20.197

• -disubstituted olefins is observed and interpreted as evidence that aziridination proceeds via a carbocation intermediate that subsequently cyclizes. These results demonstrate a simple method for activating iminoiodinane reagents, provide analysis of the extent of activation achieved by H-bonding, and indicate

• iminoiodinane reacts directly with the olefin to generate a short-lived alkyl-bound iodinane 7 or iodonium species 8 (Scheme 4f). Ligand coupling from 7 or extrusion of iodobenzene from 8 would furnish a carbocation intermediate 9 which could undergo C–C bond rotation prior to ring closure to form the aziridine

gem-Difluorination of carbon–carbon triple bonds using Brønsted acid/Bu₄NBF₄ or electrogenerated acid

• Mizuki Yamaguchi,
• Hiroki Shimao,
• Kengo Hamasaki,
• Keiji Nishiwaki,
• Shigenori Kashimura and
• Kouichi Matsumoto

Beilstein J. Org. Chem. 2024, 20, 2261–2269, doi:10.3762/bjoc.20.194

• electricity was passed to the solution. A plausible reaction mechanism for the current reactions is described in Scheme 3. The reaction of carbon–carbon triple bonds and H+ species, which are derived from the Brønsted acid (in method A) or EGA (in method B), gives the vinylic carbocation intermediate A, which

• can react with BF4− to give fluorinated alkene B [57][58][59][60]. In the next step, B can undergo the second addition of H+, followed by the incorporation of F− into the carbocation intermediate C, forming the difluorinated compound 2a. The carbocation adjacent to the F atom might be stabilized by

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• above and on literature precedents [40][41], a plausible mechanistic pathway for the formation of 2 and 3 is shown in Scheme 5 (with the reaction of 1a as an example). In the presence of DBSA, the protonation of 1a results in the carbocation intermediate I. Then, the nucleophilic attack of H2O at the

• carbocation of I produces intermediate II, which converts into intermediate III through a deprotonation–protonation process. Finally, the elimination of PhNH2 from intermediate III occurs to afford the desired product 2a. In the presence of NaOH, the Michael addition between 1a and base initially occurs to

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

• primarily resulted in the formation of isomers 74, in which the positive carbocation of the ylide was attacked by the double bond of methylene (C-161), followed by the addition of the negative oxygen atom of the dipole. This cycloaddition occurred highly selectively on the α-side of the double bond. Minor

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

• skeletal rearrangement, providing the distinct skeleton of 11 via carbocation C. This rearrangement involves the preferential migration of an alkenyl group in C to the carbocation, followed by deprotonation at C18 to form an exo-olefin. β-face-selective hydroxylation at C12 in 11 by the P450 enzyme BscG

• in unexpected conversions, including the formation of an allylic carbocation at C1, followed by transannular hydride transfer from C8 to afford ketone 20 in 62% yield. With the 5/8/5 tricyclic scaffold 20 in hand, site- and diastereocontrolled C9 hydroxylation of 20 produced a substrate 21 for the

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• and 30). In these cases, a carbocation-involved pathway may be operative to yield the product. The successful and exclusive observation of product 29, however, provided a piece of evidence to the objection of this possibility, as no carbocation-based rearrangement product was observed in our reaction

Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner–Meerwein rearrangement

• Ziya Dağalan,
• Muhammed Hanifi Çelikoğlu,
• Saffet Çelik,
• Ramazan Koçak and
• Bilal Nişancı

Beilstein J. Org. Chem. 2024, 20, 1462–1467, doi:10.3762/bjoc.20.129

• selectfluor and a carbocation is formed by bonding with fluorine. Subsequently, fluoroalkoxy compound 4 is formed by Wagner–Meerwein rearrangement followed by alcohol addition and deprotonation. Conclusion New bicyclic fluoroalkoxy compounds were synthesized by a molecular fluorine and metal-free methodology

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights

• Amol P. Jadhav and
• Claude Y. Legault

Beilstein J. Org. Chem. 2024, 20, 1286–1291, doi:10.3762/bjoc.20.111

• side products is proposed through path b (Scheme 3). The elimination of α-proton on the side chain of dialkyl bromoalkenes results in iodonium intermediate D, which on the expulsion of PhI gives a mixture of the allylic carbocation E, which ultimately gets trapped by MeCN in the presence of H2O, giving

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• the germacrene A and hedycaryol-derived carbocations. This study focused on twelve hydrocarbons derived from germacrene A and twelve from hedycaryol, which can be divided into three groups: four molecules containing 6-6 bicyclic rings, four 5-7 bicyclic compounds with the carbocation being on the

• seven-membered ring and the remaining four 5-7 bicyclic compounds with the carbocation on the five-membered ring. The variations in energy within the groups of carbocations (i.e., 6-6 and two kinds of 5-7 bicyclic carbocations) can be ascribed to intramolecular repulsion interactions, as seen from non

• derived from germecrene A. Keywords: carbocation; germacrene A; hedycaryol; stability trend; terpenes; Introduction Terpenoids form a large and highly diverse group of natural products with a wide range of usage in the pharmaceutical, cosmetic, agricultural, food, and energy industry. Among their

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• they often synthesize multiple products from a single substrate through complex cyclization cascades [4][5][6][7][8][9][10]. Based on the mechanism of initial carbocation generation, TSs generally fall into two main classes. Class I TSs generate an allylic cation from a prenyl substrate by

• depyrophosphorylation, whereas class II TSs utilize a general acid (a key Asp residue) to protonate the terminal C=C bond or epoxide group to yield a tertiary carbocation. The highly reactive carbocation is then converted to different carbocation intermediates, facilitated by the hydrophobic pocket of the TSs, which

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• the observed retention of configuration, showing that substantial interactions between the oxygens of the ring and centres on the larger bridge are possible [32]. The specificity of the rearrangement also eliminates the possibility of an intermediate secondary C4 carbocation, and requires a concerted

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• the alkene in the first step, providing a carbocation that subsequently reacts with a chloride anion to yield the Markovnikov product. While this ionic mechanism is commonly illustrated in textbooks by showing “naked” cations as intermediates, several recent studies suggest a molecular concerted or

• ) [78]. Another advantage of the MH HAT process is that the α-C–H bond in the corresponding radical is comparatively stable, whereas a carbocation has superacidic α-C–H bonds with a pKa of ≈ −17 [79]. Therefore, polar hydrochlorination reactions are in competition with elimination reactions which is not

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

• Fumito Sato,
• Terutaka Sonohara,
• Shunta Fujiki,
• Akihiro Sugawara,
• Yohei Morishita,
• Taro Ozaki and
• Teigo Asai

Beilstein J. Org. Chem. 2024, 20, 714–720, doi:10.3762/bjoc.20.65

• complexity. TCs are generally classified into two main classes, class I and class II. Class I TCs initiate the cyclization by heterolytic cleavage of substrates to generate a diphosphate anion and an allylic carbocation, and class II enzymes start cyclization by protonating a double bond or an epoxide

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• , further oxidation would generate the corresponding carbocation, which upon reaction with a nucleophilic alkyne would form the product (Scheme 1B, reaction 3). Based on precedence in the literature, this method should allow to transfer efficiently both aryl- and alkyl-substituted alkynes [41][42][43][44

• ]. On the other hand, the nature of the alkene might be limited as it would strongly influence the oxidation potential of the carbon radical and the stability of the resulting carbocation. Recently, we reported the first successful application of an RPC strategy for the azido-alkynylation of styrenes

• since it is known to be reduced by photocatalysts such as Cu(dap)2Cl [17]. This perfectly fits a catalytic cycle involving the reduction of Ts-ABZ (3) followed by oxidation of the carbon radical to form a carbocation and regenerate the ground state catalyst. Styrene (1a) was used as model substrate

Tandem Hock and Friedel–Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

• Viktoria A. Ikonnikova,
• Cristina Cheibas,
• Oscar Gayraud,
• Alexandra E. Bosnidou,
• Nicolas Casaretto,
• Gilles Frison and
• Bastien Nay

Beilstein J. Org. Chem. 2024, 20, 162–169, doi:10.3762/bjoc.20.15

• oxocarbenium 7 and 7’ which exists as a stabilized form including an intramolecular stabilizing interaction between the carbocation and the ester carbonyl group. However, in close agreement with Hess and Baldwin’s values found for the rearrangement of cis-1,3-pentadiene [24], this transition state was high in

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• cyclization reactions involve a number of carbocation intermediates. In some cases, these carbocations are stabilized by through-space interactions with π orbitals. Several terpene/terpenoids, such as sativene, santalene, bergamotene, ophiobolin and mangicol, possess prenyl side chains that do not participate

• possibility of through-space interactions with prenyl side chains using DFT calculations. Our calculations show that (i) the unstable secondary carbocation is stabilized by the cation–π interaction from prenyl side chains, thereby lowering the activation energy, (ii) the four-membered ring formation is

• completed through bridging from the exomethylene group, and (iii) the annulation from the exomethylene group proceeds in a barrier-free manner. Keywords: biosynthesis; carbocation; cation–π interaction; DFT; terpene; Introduction Terpene/terpenoids are most abundant natural products in nature, more than

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

• conversion of 1-I to 2-II was confirmed by mechanistic studies due to the stability of the benzyl carbocation, followed by 6-endo-dig cyclization. In this method, toxic transition metal catalysts, oxidants, or bases are not used, which made it economically and environmentally reliable. In 2023, Gao et al

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• ) process, the carbocation intermediate B is generated, which is attacked by a nucleophile to afford the target product. Further, C–H bonds in the ortho-position of a heteroatom are activated through a SET pathway generating a radical cation C, which is easily deprotonated by an oxidant to generate a

• carbocation D. Finally, the nucleophile attacks the carbocation D, to obtain the final coupled product. The deprotonation of the nucleophile occurs before or after the attack on the carbocation intermediate, depending on the acidity of the nucleophile. In 2008, Li et al. reported that Fe2(CO)9 as a catalyst

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• elimination-like pathway to afford unsaturated C–C bonds in the presence of copper(II) sulfate, presumably via competitive RPC to the carbocation followed by E1 olefination. Kochi also demonstrated that RLT can be combined with other radical generation strategies to enable new, non-biomimetic reactions to be

• (XAT) from the alkyl halide reagent and further oxidation of the transient radical to a carbocation by radical polar crossover (RPC), providing two mechanistic pathways to form the ATRA products [32]. While powerful, this approach is inherently incompatible with introducing alternative functionality

• proposed to follow one of two pathways: formation of a carbocation through RPC followed by nucleophilic attack or direct RLT from a redox-active metal complex. Preliminary evidence for a radical decarboxylation/RLT cascade was reported in 1965, when Kochi demonstrated decarboxylative chlorination of