Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• CO, Jiang and co-workers (2020) reported a Pd-catalyzed hydrocarboxylation of alkynes with high regioselectivity to obtain the corresponding cinnamic acids 281 and 282 in good yields via cyclopalladation intermediate 283 (Scheme 70A) [119]. The method has been scaled up to a gram scale operation

Recent total synthesis of natural products leveraging a strategy of enamide cyclization

• Chun-Yu Mi,
• Jia-Yuan Zhai and
• Xiao-Ming Zhang

Beilstein J. Org. Chem. 2025, 21, 999–1009, doi:10.3762/bjoc.21.81

• ring was then constructed via an intramolecular reductive Heck reaction from vinyl bromide 10 with exclusive regioselectivity. Considering the strain of forming the 7-membered ring, this highly efficient 7-endo-trig (vs 6-exo-trig) transannular Heck cyclization reaction was remarkable to be realized in

Harnessing tethered nitreniums for diastereoselective amino-sulfonoxylation of alkenes

• Shyam Sathyamoorthi,
• Appasaheb K. Nirpal,
• Dnyaneshwar A. Gorve and
• Steven P. Kelley

Beilstein J. Org. Chem. 2025, 21, 947–954, doi:10.3762/bjoc.21.78

• Abstract We present the first examples of alkene amino-sulfonoxylation reactions that leverage the unique reactivity of carbamate tethered N-alkoxy nitrenium ions. In almost all cases examined, the reactions deliver product with exquisite regioselectivity and diastereoselectivity. The protocols followed

• new alkene amino-sulfonoxylation reaction that leverages the unique reactivity of carbamate tethered N-alkoxy nitrenium ions. In almost all cases examined, the reactions delivered product with exquisite regioselectivity and diastereoselectivity. The protocols followed were operationally very simple

A convergent synthetic approach to the tetracyclic core framework of khayanolide-type limonoids

• Zhiyang Zhang,
• Jialei Hu,
• Hanfeng Ding,
• Li Zhang and
• Peirong Rao

Beilstein J. Org. Chem. 2025, 21, 926–934, doi:10.3762/bjoc.21.75

• promoted by LiHMDS gave alcohol 17 with high regioselectivity (14:1 dr at C17) after an extensive screening of bases (LDA, NaHMDS, KHMDS, etc.). Drawing inspiration from the pioneering work of Birman [38], as well as Newhouse’s applications [18][19], an acylative kinetic resolution of the alcohol was

Recent advances in controllable/divergent synthesis

• Jilei Cao,
• Leiyang Bai and
• Xuefeng Jiang

Beilstein J. Org. Chem. 2025, 21, 890–914, doi:10.3762/bjoc.21.73

• ensuring high regioselectivity. In 2018, the Jiang group developed a regiodivergent synthetic method for indolo[3,2-c]coumarins 10 and benzofuro[3,2-c]quinolinones 9 via controllable palladium(II)-catalyzed carbonylative cyclization (Scheme 3) [21]. When ligand L3 coordinates with the palladium center, the

• , the Shu group developed a catalyst-controlled regioselective and enantioselective hydroamination reaction of electron-deficient alkenes (Scheme 7) [30]. By efficiently regulating the regioselectivity and enantioselectivity of alkene 23 hydrometallation through catalytic systems, they overcame the

• obtained with exclusive regioselectivity and excellent enantioselectivity. Employing a nickel catalyst, α-chiral β-amino acid derivatives 27 were synthesized with single regioselectivity and outstanding enantioselectivity. In the same year, Rong and co-workers reported a highly efficient catalyst

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• the copper–boron bond into 1. The dual functionality of this substrate imposed a question related to the regioselectivity of the Cu–Bpin insertion since it can potentially behave as an α,β-unsaturated ester or an allylic substrate [16][17][18][19]. To shed some light into this issue, we ran the

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• catalysis; hydrocyanation; regioselectivity; tosyl cyanide; Introduction Acyclic nitriles that incorporate α-all-carbon quaternary centers are highly valuable structural motifs typically found in natural products, biologically active compounds, and synthetic pharmaceuticals [1][2][3][4][5]. These compounds

• ]. The limited investigation of allene hydrocyanation can be attributed to the significant challenges posed by the two orthogonal π-systems in allenes. These challenges include achieving high regioselectivity and controlling (E)/(Z)-stereoselectivity, as 1,2-addition processes to allenes can generate up

• for the in situ generation of hydrogen cyanide (Scheme 1a). This method achieved high regioselectivity and enantioselectivity, highlighting the potential of allene hydrocyanation for the synthesis of complex nitrile-containing products. In another approach, the Minakata group used electrophilic

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• ferrocene and ruthenocene via coupling reaction. This method provides an efficient and versatile synthetic approach for producing phosphorylated metallocenes but also aids in interpreting the regioselectivity and reactivity of C−H functionalization in unsymmetric metallocenes. They used a platinum electrode

• , or phenyl groups at the α-position. The researchers noted that the lower yields were due to substrate decomposition or poor conversion rather than regioselectivity issues. Additionally, this method was also suitable for the phosphorylation of ferrocenes. For mechanistic studies, the reaction was

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• eponymous Tsuji–Trost reaction, they faced a significant limitation: poor regioselectivity with non-symmetrical allylic substrates 2. This constraint led to the predominant development of Pd-catalyzed methods using symmetric 1,3-disubstituted allylic substrates 1 that contain a leaving group in the allylic

• substitution reactions began to develop with the groundbreaking work of Takeuchi and Kashio, and subsequent research has revealed that iridium catalysts behave quite differently from their palladium counterparts [18]. The most notable distinction lies in their contrasting regioselectivity patterns. Palladium

• regioselectivity (SN2/SN2' = >99:1). The reaction with 3-methylbut-2-en-1-yl bromide (15) was particularly noteworthy, as it exhibited superior selectivity compared to the corresponding phosphates. The high efficiency of this protocol was demonstrated through the synthesis of various functionalized alkenes with

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

• catalysis, respectively [86][93]. They extended the scope of the reaction to a wider range of amidines and isocyanides using glyoxylic acid in 50% aqueous solution, with HClO4 as acid catalyst (Scheme 35) [86]. Under these conditions, the yield, the scope, and the regioselectivity of the reaction increased

Vinylogous functionalization of 4-alkylidene-5-aminopyrazoles with methyl trifluoropyruvates

• Judit Hostalet-Romero,
• Laura Carceller-Ferrer,
• Gonzalo Blay,
• Amparo Sanz-Marco,
• José R. Pedro and
• Carlos Vila

Beilstein J. Org. Chem. 2025, 21, 533–540, doi:10.3762/bjoc.21.41

• biologically active compounds, particularly antibacterial and antifungal agents [13][14]. This class of functionalized nitrogen heterocycles is notable for its synthetic versatility, because it shows different nucleophilic positions, making regioselectivity a synthetic challenge. Numerous studies have reported

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• hydrophobic catalysis as for the macrocycles discussed in the previous section [115], and so remain prone to product inhibition [113], though not exclusively [120]. Size- and regioselectivity are possible [121]. As with the two identical halves of a tennis ball/softball, it is harder to conceive unsymmetric

Three-component reactions of conjugated dienes, CH acids and formaldehyde under diffusion mixing conditions

• Dmitry E. Shybanov,
• Maxim E. Kukushkin,
• Eugene V. Babaev,
• Nikolai V. Zyk and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 262–269, doi:10.3762/bjoc.21.18

• cyclohexadiene did not react even with acetylacetone, and for 2,3-dimethylbutadiene, target compound 13 was obtained in 41% yield. In all cases, no formation of even trace amounts of the hetero-Diels–Alder reaction adducts II was detected. The regioselectivity of the cycloaddition of methylidene intermediates

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• -fluorobenzene (see Scheme 2 and Supporting Information File 1 for details). Copper(I)-catalyzed three-component coupling reaction of alkyne 8, THIQ 9, and benzaldehyde, proceeded with exquisite control of regioselectivity to afford 10 in an excellent yield of 92% [43][44][45][46]. This efficient cascade

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• potential bioactivity [70][71][72][73]. Despite the development of synthetic approaches for six-membered lactams, including transition-metal-catalyzed transformations, several limitations remain, particularly with regard to regioselectivity and asymmetric C–N bond formation, which are still limited. In 2023

• lactams in high yields and excellent enantioselectivities (2a, 2b, and 2d). It was observed that the steric environment affected both reactivity and enantioselectivity (2c). Six-membered lactams featuring propargylic (2e) and alkenyl (2f) motifs were also obtained with excellent regioselectivity and

• dioxazolone bearing a linear alkyl group was efficiently converted to the N-vinylamide 26a in good yield. The observed regioselectivity followed the anti-Markovnikov fashion stemming from the regioselective hydrozirconation of the alkyne using Schwartz’s reagent [100]. Aryl substituents on the dioxazolone

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• esters containing a quaternary stereocenter, and the control of regioselectivity depended on the bulkiness of the substrates. Additionally, the electrochemical system served as an internal syringe pump, generating quinone from hydroquinone in situ through anodic oxidation, which enhanced the

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

• is plausible to assume as the key step for ring formation an aza-Diels–Alder reaction between the alkyne and the imine generated by dehydration between the aldehyde and aniline. The catalyst promotes the formation of the imine XI, while the high regioselectivity is ascribable to the favored

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

• -naphthols, new atroposelective reactions of quinones and iminoquinones were developed [63]. The reaction of quinones with an ester group 109 and indoles with alkyl substituents 110 catalyzed by CPA C29 provided products 112 with regioselectivity on the pyrrole ring of indole (Scheme 35). On the contrary

• , adding a hydroxy group to the benzene ring of indoles 111 and reacting them with tosyl-protected iminoquinone 109 with the help of CPA C30 led to the shift in regioselectivity providing different axially chiral products 113. All products were obtained with high degree of enantiomeric purity as well as

• in the regioselectivity change. Song et al. broadened the scope of usable substrates for the asymmetric arylation of naphthoquinones 115 with indolizines 114 catalyzed by CPA (R)-C23 forming atropoisomers 116 (Scheme 36) [64]. A broad range of indolizine substrates was tested with substituents in

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• the regioselectivity of the reaction when 3-pyridylboronic acid is used as substrate as there are two different positions (C2 and C4) on the pyridine ring available for the C–H arylation step. Interestingly, azafluoranthene 15h was obtained as the only product in this reaction, albeit in a lower yield

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• HVI reagent has also shown to dictate the regioselectivity of the reaction. Future research efforts should focus on further developing access to new heterocycles, as well as designing better systems to incorporate high levels of diastereoselectivity and enantioselectivity into chiral halogenated

Enantioselective regiospecific addition of propargyltrichlorosilane to aldehydes catalyzed by biisoquinoline N,N’-dioxide

• Noble Brako,
• Sreerag Moorkkannur Narayanan,
• Amber Burns,
• Layla Auter,
• Valentino Cesiliano,
• Rajeev Prabhakar and
• Norito Takenaka

Beilstein J. Org. Chem. 2024, 20, 3069–3076, doi:10.3762/bjoc.20.255

• propargyltrichlorosilane without N,N-diisopropylethylamine and (b) with N,N-diisopropylethylamine. It includes Gibbs free energies (kcal/mol) and Mulliken charges (in parentheses). Metallotropic rearrangement and regioselectivity issues. Asymmetric catalytic allenylation of aldehydes. Selective preparation of

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

• regioselectivity of attachment to a double bond with a neighboring electron-withdrawing group was found (Scheme 37). The in situ-generated radical species A and B abstract a hydrogen atom from the cycloalkane 105 to generate a cycloalkyl radical species C. The allylic CH2 of the indene 104 is oxidized to C=O in

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

• reductive elimination in exceptional yields (Scheme 20) [71]. Although screening studies indicated the possibility of achieving the N-arylation at both, the N1- and N2-positions of the triazoles, N2-arylation was predominantly observed. It was incredible to achieve splendid regioselectivity without the

• usage of directing groups and any metal catalyst. Also, the electronic nature of a substituent at the C4 position of the starting triazole did not negatively impact the regioselectivity. Further, C4 and C5 disubstituted triazoles also produced the N2-arylated product. Remarkably, this is the only

• diaryliodonium salts 73. Remarkably, the method exhibited high regioselectivity, with the substitution at the meta position being observed with up to 99% selectivity in comparison to the ortho position. Specifically, only electron-withdrawing groups like OMe or CF3 when substituted at the m-position relative to

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

• from p-fluoroaniline which can be explained by the π-donating effect of fluorine which facilitates the cyclization via the ortho-position in case of m-, but not of p-fluoroaniline. It is worth to be noted that the formation of 23d proceeded with excellent regioselectivity via carbon C-6 rather than C-2

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• developments and illustrates the influences of copper salt, ligand, and substitution pattern of the substrate on the regioselectivity and stereoselectivity. Keywords: copper-catalysis; copper vinyl allenylidene intermediate; 1,3-enyne; 1,4-enyne; yne-allylic substitution; Introduction Copper is earth

• nucleophiles (Scheme 1b). However, to achieve a highly selective yne-allylic substitution, a range of challenges must be addressed. First, how to achieve the regioselectivity under the coexistence of alkenyl and alkynyl units; second, how to realize the enantioselectivity control that is remote from the

• substitutions, the realm of yne-allylic substitution remains relatively unexplored. This scarcity of reports stems primarily from the inherent challenges posed by the presence of two unsaturated bonds in the substrates, which often complicates the control of regioselectivity. Additionally, the competition among