Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• -protected amino group. On the basis of the previous report [28], a possible reaction mechanism is presented in Scheme 3. The reaction of triphenylphosphine oxide and triflic anhydride first generates an activating agent, the Hendrickson reagent (A). The amide in cyclohexane-1,2-dicarboxamides 4

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• Biotin-SAC4A by modifying SAC4A with biotin. (Figure 16) [124]. Monocarboxylated azocalixarene and aminated biotin were synthesized. Subsequently, using a coupling agent, the carboxyl group of the azocalixarene was modified through amidation to obtain biotin-modified SAC4A. The formation of amide bonds

Unique halogen–π association detected in single crystals of C–N atropisomeric N-(2-halophenyl)quinolin-2-one derivatives and the thione analogue

• Mai Uchibori,
• Nanami Murate,
• Kanako Shima,
• Tatsunori Sakagami,
• Ko Kanehisa,
• Gary James Richards,
• Akiko Hori and
• Osamu Kitagawa

Beilstein J. Org. Chem. 2025, 21, 1748–1756, doi:10.3762/bjoc.21.138

• intermolecular interaction (halogen bonding) between chiral compounds possessing an amide group and a thioamide group are quite rare [21]. We were curious as to whether the chirality (racemate/optically pure form)- and the functional group (C=O/C=S)-dependent halogen bonds found in I and II are also observed in

Preparation of a furfural-derived enantioenriched vinyloxazoline building block and exploring its reactivity

• Madara Darzina,
• Anna Lielpetere and
• Aigars Jirgensons

Beilstein J. Org. Chem. 2025, 21, 1737–1741, doi:10.3762/bjoc.21.136

• ][24] (Scheme 1). The proposed strategy relied on the N-deprotection of the intermediate ester 3d inducing O-to-N rearrangement to form amide 5 as a precursor of vinyloxazoline 6. For this purpose, Alloc (allyloxycarbonyl) turned out to be a suitable N-protecting group as it was compatible with the

• trans-isomer of amide 5. Results and Discussion The protected furfuryl amino alcohols S-2d and R-2d were prepared by reductive amination of furfural (1) with ʟ- and ᴅ-valinol followed by N-protection with Alloc-Cl (Scheme 2). The amino alcohols S-2d and R-2d were then subjected to electrochemical

• material S-3d but provided a mixture of cis- and trans-amides cis-S-5 and trans-S-5 (Scheme 3). The use of PdCl2(S-BINAP) complex as a precatalyst resulted in a longer reaction time and an exclusive formation of amide trans-S-5 with isomerized double bond (Scheme 4). The amide trans-R-5 was prepared

Catalytic asymmetric reactions of isocyanides for constructing non-central chirality

• Jia-Yu Liao

Beilstein J. Org. Chem. 2025, 21, 1648–1660, doi:10.3762/bjoc.21.129

• ]. Encouraged by the above results, we turned our attention to biaryl lactams [49]. However, in this case, the inherent resonance stability of the amide bond makes the ring-opening process rather challenging. To solve this problem, we envisioned that a cooperative catalytic system merging silver catalysis and

pH-Controlled isomerization kinetics of ortho-disubstituted benzamidines: E/Z isomerism and axial chirality

• Ryota Kimura,
• Satoshi Ichikawa and
• Akira Katsuyama

Beilstein J. Org. Chem. 2025, 21, 1568–1576, doi:10.3762/bjoc.21.120

• substitution of an ortho-disubstituted benzamide (DiBA) increases the rotational barrier of the C–N and C–N/C–C concerted rotation (Figure 1a,b) [20]. The observation can be explained mainly by the double-bond nature of the chalcogen amide C–N bond, which is attributed to a zwitterionic resonance structure of

• chalcogen amide. It has been shown that a late periodic chalcogen amide has a lower energy π* orbital (C=S or C=Se), resulting in an increase in the contribution of the zwitterionic resonance structure [21][22][23]. Based on this consideration, an ortho-disubstituted benzamidine, which is generated by

• various fields, such as functional materials, biological probes, and drugs. a) Structural features of DiBA. b) Resonance structure of the amide moiety of DiBA. c) Molecular form and protonated structure of ortho-disubstituted benzamidine. Rotational barriers of 2-bromo-N,N,6-trimethylbenzimidamide and its

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• , a wide range of organic reactions, e.g., urea and amide formation [32][33], amide coupling [34], aldol condensation [35], C–H difluoromethylation [36], aromatic substitution [37], and MOFs synthesis [38] were demonstrated in CyreneTM. Very recently, Fasano and Citarella first reported a CuAAC

Photoredox-catalyzed arylation of isonitriles by diaryliodonium salts towards benzamides

• Nadezhda M. Metalnikova,
• Nikita S. Antonkin,
• Tuan K. Nguyen,
• Natalia S. Soldatova,
• Alexander V. Nyuchev,
• Mikhail A. Kinzhalov and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2025, 21, 1480–1488, doi:10.3762/bjoc.21.110

• bioactive compounds. According to the DrugBank there are more than 250 approved drugs classified as amides [2]. Just recently, between February 2021 and June 2022, sixteen anticancer drugs containing an amide bond have been approved by the U.S. FDA [3]. Consequently, the preparation of amides has garnered

• significant attention within organic and medicinal chemistry. Commonly, amide bonds are formed via the reaction of carboxylic acids or their derivatives with appropriate amines (Scheme 1A) [4]. Although this conventional approach is effective and straightforward, it usually suffers from harsh conditions and

• % yield. Competing amide 2bn was not detected in the reaction mixture even by GC–MS analysis. In contrast, the mesityl-substituted salt 1l gave both competing products 2ba and 2bk in a ≈4:1 ratio, while the 2,4,6-triisopropylphenyl derivative 2bm yielded a mixture of products 2ba and 2bm in low yield

Copper catalysis: a constantly evolving field

• Elena Fernández and
• Jaesook Yun

Beilstein J. Org. Chem. 2025, 21, 1477–1479, doi:10.3762/bjoc.21.109

• by Son and co-workers illustrates recent advancements in the use of dioxazolones in synthetic transformations with copper salts [4]. The authors remark that these catalytic systems, which employ dioxazolones as electrophilic amide sources, were applied for the preparation of diverse amidated products

Advances in nitrogen-containing helicenes: synthesis, chiroptical properties, and optoelectronic applications

• Meng Qiu,
• Jing Du,
• Nai-Te Yao,
• Xin-Yue Wang and
• Han-Yuan Gong

Beilstein J. Org. Chem. 2025, 21, 1422–1453, doi:10.3762/bjoc.21.106

• optoelectronic materials. In 2022, Furuta’s group developed a one-pot synthetic protocol to access (NH)-phenanthridinone derivatives and chiral amide-functionalized [7]helicene-like molecules 67a,b from biaryl dicarboxylic acids, employing a Curtius rearrangement followed by basic hydrolysis [81] (Table 23

N-Salicyl-amino acid derivatives with antiparasitic activity from Pseudomonas sp. UIAU-6B

• Joy E. Rajakulendran,
• Emmanuel Tope Oluwabusola,
• Michela Cerone,
• Terry K. Smith,
• Olusoji O. Adebisi,
• Adefolalu Adedotun,
• Gagan Preet,
• Sylvia Soldatou,
• Hai Deng,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2025, 21, 1388–1396, doi:10.3762/bjoc.21.103

• (δH 1.10, d, J = 6.9 Hz) revealed the presence of a threonine moiety in 1. Strong HMBC correlations from H-5, H-8 and H-9 to the carbonyl carbon C-7 (δC 167.2) confirmed an amide bond by which the salicylic acid and threonine residues were linked. The deshielded carbon signal at δC 172.9 was assigned

• H-11 to C-10 (δC 173.5), H3-12 to C-9 (δC 128.1) and C-11 (δC 133.9). The relative stereochemistry of the double bond of the dehydrobutyrine moiety was established as Z based on a medium NOE correlation observed between the amide proton, H-8 (δH 9.82) and the methyl protons, H3-12 (see Figure 2 and

• configuration to that of 3, evidenced by a medium through space correlation between the amide proton, H-8 (δH 9.9) and the methyl, H3-12 (δH 1.76) in the NOESY spectrum (see Figure 2 and Supporting Information File 1, Figure S23). Based on HRESIMS, 1D and 2D NMR data, the structure of compound 4, was confirmed

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• -aminooxetanes 169 through a defluorosulphonylative coupling of sulphonyl fluorides 168 (Scheme 41) [92]. Because this novel methodology mimics the classical amide coupling strategy, it allows for a direct use of the established amine libraries and thus provides a rapid access to benzamide bioisosteres. The

• nucleophiles, thus providing access to oxetane sulphonamides, sulphonyl azides, sulphonates and sulphones [93]. In 2024, Soós et al. published a similarly mild protocol for the synthesis of amide bioisosteres which utilises Katritzky’s benzotriazole chemistry (Scheme 42) [94]. Unlike the Bull’s methodology

• to a potentially even larger library of amide isosteres. The scope of the carbon nucleophiles is very broad and includes alkyls, alkenyls, alkynyls, aryls and heteroaryls (e.g., pyridine, indole, thiophene), as well as (poly)substituted phenyls bearing a nitrile or halogen(s). On the other hand, the

Recent advances in amidyl radical-mediated photocatalytic direct intermolecular hydrogen atom transfer

• Hao-Sen Wang,
• Lin Li,
• Xin Chen,
• Jian-Li Wu,
• Kai Sun,
• Xiao-Lan Chen,
• Ling-Bo Qu and
• Bing Yu

Beilstein J. Org. Chem. 2025, 21, 1306–1323, doi:10.3762/bjoc.21.100

• ]. The electron-withdrawing groups could stabilize the charge of the N-centered radical during the HAT process by decreasing the charge density [44]. Notably, the BDE of N–H in the corresponding amide might be too low to ensure a spontaneous HAT process due to the electronic effect of the substituent

• amidyl radicals from HRP: (a) direct single-electron oxidation of amide HRP in the presence of photocatalyst and a base via a proton-coupled electron transfer (PCET) process by the cleavage of the N–H bond; (b) single-electron reduction of HRP catalyzed by photocatalyst via a single-electron transfer

• (SET) process by the cleavage of the N–O bond; (c) direct homolytic cleavage of weak N–S or N–X bonds in HRP initiated in the presence of visible light; (d) the intersystem crossing (ISC) of S1 to T1 state directly from the amide anion. This review is organized by bond cleavage type, offering a deep

Recent advances in oxidative radical difunctionalization of N-arylacrylamides enabled by carbon radical reagents

• Jiangfei Chen,
• Yi-Lin Qu,
• Ming Yuan,
• Xiang-Mei Wu,
• Heng-Pei Jiang,
• Ying Fu and
• Shengrong Guo

Beilstein J. Org. Chem. 2025, 21, 1207–1271, doi:10.3762/bjoc.21.98

• different alkyl substituents at the α-position of the 1,3-dicarbonyl compounds, including functionalized alkyl chains with alkenyl, alkynyl, and aryl groups, all of which were compatible with the reaction conditions. Interestingly, when α-alkylmalonic esters were employed instead of malonate amide moieties

• experiments and cyclic voltammetry (CV) indicated that the reaction mechanism proceeds via a radical pathway. DFES-Na undergoes single-electron oxidation at the anode, generating a radical that reacts with the olefinic amide, followed by intramolecular cyclization to form the target difluoroalkylated

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• macrolides with hydroxy groups at C20 or C7, identified as borrelidins C–E (Table 1, entries 4, 7, and 8) [19]. Borrelidins CR1 and CR2 (Table 1, entries 5 and 6), amide-containing congeners, were also isolated through bioassay-guided fractionation and purification of marine microorganisms from Costa Rica

• acid, and protection of the secondary alcohol as a TBDMS ether (Scheme 9). Intermediate 63 was planned to be derived from Evans’ amide 64 by reducing the amide moiety to a primary alcohol, oxidizing it to an aldehyde, performing a Wittig olefination to install an unsaturated ester, reducing the ester

• to a primary alcohol, and then conducting asymmetric epoxidation of the double bond. Evan’s amide 64 would be synthesized from primary alcohol 65 through a sequence of oxidation to aldehyde, Wittig olefination to an unsaturated ester, hydrogenation of the olefin, conversion of the ester to Evans

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• derivatives exclusively leads to a cis-amide bond [57]. Most noteworthy are the signals of both protons H2 and H6, which display a different coupling pattern and a notable shift around 1 ppm upfield for H2 and around 1 ppm downfield for H6. Examination of the coupling constants of both these protons shows

• in the amide bond and their resulting restraints. The coupling patterns of H2 and H6 do not change upon hydrolysis of the methyl ester, resulting in product (2R,6S)-10, where the second set of signals still remains (Figure 2b). However, cleaving the formyl group, on the other hand, leads to product

Supramolecular assembly of hypervalent iodine macrocycles and alkali metals

• Krishna Pandey,
• Lucas X. Orton,
• Grayson Venus,
• Waseem A. Hussain,
• Toby Woods,
• Lichang Wang and
• Kyle N. Plunkett

Beilstein J. Org. Chem. 2025, 21, 1095–1103, doi:10.3762/bjoc.21.87

• almost the same. In this complex, the Na+ is similarly coordinated with two phenylalanine macrocycles through the amide moiety carbonyl oxygen (O9 from one I and O12 from second I). However, the bond distances between oxygen and the metal are significantly longer for Na+ versus Li+. The O9–Na distance is

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

• 2.1.1 Stoichiometric reagents: Anhydride formation is one reliable method to activate the carboxylic group of cinnamic acid. For instance, in 2020, Longobardo and DellaGreca utilized isobutyl chloroformate in water to construct an O-protected amide derivative 2 of hydroxycinnamic acid 1 with an

• excellent yield (Scheme 2) [32]. The formed anhydride 3 was smoothly converted to the amide at room temperature. This method provides a green approach by allowing cinnamic acid derivatization in water as a benign solvent. Similarly, Rajendran and Rajan (2023) reported a one-pot transamidation of cinnamamide

• 4 by utilizing pivaloyl chloride via the N-pivaloyl-activated amide 6 to give piperlotine A (5), the secondary metabolite of black pepper (Piper nigrum) reported to show antibacterial and bioinsecticidal activities, in good yield (Scheme 3A) [33][34]. In the akin process, Xu and co-workers (2023

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• reaction with nucleophilic lithium amide from n-propylamine, the reduction of phosphine oxide 9 by trichlorosilane/triethylamine, and the N-acylation of 10 with cinnamoyl chloride in three steps (Scheme 1). We also analyzed amide compound 7 by HPLC analysis using a chiral stationary phase column with a CD

• detector and found that the C(aryl)–N(amide) bond axial chirality exists in amide compound 7. We attempted the optical resolution of racemic compound (±)-7 and obtained (+)-7 and (−)-7 using a semi-preparative chiral HPLC on 50 milligram scales. We also investigated the racemization process associated with

• steps from phosphine oxide 8. Chiral HPLC analysis confirmed its axial chirality at the C(aryl)–N(amide) bond. The optical resolution of (±)-7 yielded (+)-7 and (−)-7. The racemization barrier of (−)-7 in n-dodecane was determined to be 25.0 kcal/mol at 25 °C, with a half-life of approximately 1.3 days

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

• enamides contain an N-acyl group in place of the original alkyl group. The electron-withdrawing effect of the amide group delocalizes the nitrogen lone pair, thereby reducing the electron density and nucleophilicity of the enamide double bond. These features significantly diminish the reactivity of

• iminium intermediates can serve as electrophiles. Due to the presence of an amide, the resulting iminiums from the enamides can be stabilized to take part in the second nucleophilic addition, though direct isomerization of the iminiums to the enamides is also possible (Figure 1). Guided by these

• aldol condensation of 5 provided the tetracyclic α,β-unsaturated enone 6 in 57% yield. Subsequent catalytic hydrogenation using Pd/C conditions delivered the hydrogen to the alkene from the less hindered face, producing ketone 7 with high diastereoselectivity. Final reduction of both the amide and

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• -acting, potent tranquilizer with moderate duration, belonging to the triazolobenzodiazepine family [10]. It is derived through bioisosteric replacement of the benzodiazepine amide moiety with a triazole ring. Replacements of the benzene ring with thiophene and even with pyrrole are also known. Premazepam

• , obtaining a separable mixture of the major cis and minor trans diastereomers of the sp3-enriched pyrazolodiazepine 17. The relative configuration of the stereocenters in the major cis isomer of 17 was established via scXRD analysis. Both diastereomers of 17 were found to be amenable to chemoselective amide

• reduction with LiAlH₄, which led to a further decrease in the degree of unsaturation of the pyrazolodiazepine core, while the more sterically hindered exocyclic amide moiety remained intact. However, both reactions were accompanied by partial epimerization, and careful kinetic control was therefore required

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

• weakly coordinating OTf− anion synergistically enhanced the electrophilicity of the gold center, enabling coordination with the amide group to form a three-coordinate Au(I)–π-alkyne intermediate Int-12. The umbrella-shaped steric shielding provided by the ligand-stabilized intermediate Int-9, followed by

• hydrogen atom transfer (HAT)/chiral copper dual catalytic system that achieved regiodivergent and enantioselective C(sp3)–C(sp3) and C(sp3)–N oxidative cross-couplings between N-arylglycine ester/amide derivatives and abundant hydrocarbon C(sp3)–H feedstocks (Scheme 6) [24]. This methodology also

• nucleophilic addition, and subsequent release of one molecule of amide, reactivating the active ruthenium(II) catalyst. In contrast, for diazomalonates, intermediate Int-78 releases ammonia with the help of Ru(II) or acetic acid, ultimately yielding 3H-indole 80. This change in selectivity may be due to 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

• remaining DIBAL-H and TsCN, ultimately yielding the cyanation product 5b in only 54%. The synthetic potential of the obtained β,γ-unsaturated nitriles featuring α-quaternary carbon centers was further illustrated using a series of transformations (Scheme 6). Nitrile 3q was hydrolyzed to amide 6 in a 90

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

• platinum electrode as a cathode is very suitable for the process. Increasing the contact surface of the anode using a graphite felt electrode instead of a graphite rod in the reaction medium was one of the ways to improve the result. In 2023, Wang et al. [46] reported an electrochemical reaction of amide

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• planar conformation, whereas in the fluorinated macrocycle 49, the aryl ether moiety adopts an orthogonal conformation which necessitates substantial reorganisation elsewhere in the macrocycle including a cis-amide on the opposite side of the molecule. We now consider what happens if fluorine is