One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• reaction for the synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline scaffolds 6 and 8 (Scheme 3). The first step is the Ugi-azide reaction of a 2-bromobenzoaldehyde 1, allylamine hydrochloride (2), azidotrimethylsilane (TMSN3, 3), and an isocyanide 4 affording tetrazoles 5. If ethyl isocyanoacetate is

• compound 6d (left) [CCDC: 2164364] and 8c (right) [CCDC: 2321622]. The Ugi and Ugi-azide reactions. Ugi-azide and post-condensation reactions for the synthesis of various heterocyclic scaffolds. One-pot synthesis of tetrazolyl-1,2,3,4-tetrahydroisoquinoline. One-pot synthesis of tetrazolo-pyrazino[2,1-a

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• development of these important bioisosteres. We will highlight both the synthetic routes used to access the proposed bioisosteric scaffolds, as well as any subsequent derivatization thereof which help expand their utility. Our aim is to provide an overview of the types of scaffold that can be prepared with

• isosteres and bioisosteres. Scaffolds suggested for the replacement of ortho- or meta-benzenes shall be defined as a geometrical isostere if they exhibit similar geometric properties to the parent compound. A scaffold shall be defined as a bioisostere only if both its geometrical properties and its

• biological activity are similar to the parent compound. For simplicity, geometric isosteres will be simply referred to as isosteres. More densely substituted scaffolds will be briefly discussed at the end of the review. Geometrical equivalence between disubstituted benzenes and scaffolds will be quantified

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• modification of pharmaceutical scaffolds. Naturally, we were eager to acquire detailed mechanistic insights into this protocol. To validate the radical nature of this transformation, both model reactions of 1,3-diene 2a and allene 5a were terminated completely with 2.5 equiv 2,2,6,6-tetramethylpiperidinyloxyl

HPW-Catalyzed environmentally benign approach to imidazo[1,2-a]pyridines

• Luan A. Martinho and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2024, 20, 628–637, doi:10.3762/bjoc.20.55

• (insomnia). Some recent synthetic approaches to imidazo[1,2-a]pyridine scaffolds include synthetic pathways of transition metal-catalyzed reactions [14], cyclization [15], condensation [16], heteroannular [17], and photocatalytic reactions [18]. These approaches usually involve non-trivial reaction

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

• ., Saint Petersburg 191036, Russian Federation Department of Medicinal Chemistry, Institute of Chemistry, Saint Petersburg State University, 26 Universitetskiy pr., Peterhof 198504, Russian Federation 10.3762/bjoc.20.48 Abstract A facile approach to novel medicinally relevant spiro heterocyclic scaffolds

• towards spirocyclic scaffolds as a goal of great value [6][7][8][9]. A rich synthetic platform for the design of various types of spiroheterocycles is provided by cyclic diazo compounds [10]. Recently, we and others have demonstrated the efficient use of diazoarylidene succinimides (DAS, 1) in the

• alcohol followed by base-promoted cyclization. The procedures developed allow to obtain derivatives of such sought-after scaffolds in the field of medicinal chemistry as Δα,β-butenolides, tetrahydrofurans, and pyrans spiro-conjugated with a pyrrolidine ring. The tandem approach proposed is characterized

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• genome was initially screened using fungiSMASH to identify scaffolds/contigs encoding secondary metabolites. Scaffold MSFL01000005.1 was further investigated using FGENESH [17] to further refine gene boundaries, introns, and resulting protein sequence (Table S1, Supporting Information File 1

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

• contraction of thiepine scaffolds, fused with two or three thiophene, thiopyran or polycyclic hydrocarbon moieties [64]. Indeed, a series of polyannelated thiepine derivatives were prepared according to an original approach, consisting in the introduction of the bridging sulfur atom from the outset of the

• chalcogen extrusion thus appears as highly promising for the synthesis of conjugated materials containing thiophene or selenophene moieties. However, 1,2-dichalcogenin cycles stabilized in highly conjugated scaffolds are not easily converted by light or thermal activation, as mentioned above, and their

• temperature under neat conditions [73][74][75][76][77]. In order to promote light-induced ring contraction of 1,2-dithiin scaffolds, Furukuwa et al. explored the reactivity of precursors bearing one sulfur atom in a higher oxidation state [78]. In their synthesis of dibenzo[1,4]dithiapentalene 46, the 1,2

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

• conditions. A variety of unnatural unsymmetrical β-trifluoromethyl diacyl-β-amino esters were obtained in good yields, which are useful synthetic scaffolds [50][51][52] but difficult to obtain by other methods [53][54][55][56][57]. This work is the first example of the reaction of β-trifluoromethyl β-diazo

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

• ; carbonylative cyclization; Chan–Lam; nitrogen heterocycle; one-pot; Introduction Dibenzodiazepine units are without doubt highly privileged structures, endowed with numerous medicinally relevant properties, and notably include anti-anxiolytic and antidepressant activities. These scaffolds have received much

• proven to act as p21-activated kinase (PAK) inhibitors [6], and Chk1 inhibitors [7]. The abovementioned pharmaceutical properties of the dibenzodiazepinone class have driven the development of novel synthetic strategies leading to these scaffolds in a step-economical and greener manner. Our previous

• approaches resulted in shortening the synthetic routes that were widely employed to access these heterocyclic scaffolds. Over the last decades, the Chan–Lam coupling reaction has drawn great attention among the synthetic chemistry community which contributed to the development of various synthetic routes to

Multi-redox indenofluorene chromophores incorporating dithiafulvene donor and ene/enediyne acceptor units

• Christina Schøttler,
• Kasper Lund-Rasmussen,
• Line Broløs,
• Philip Vinterberg,
• Ema Bazikova,
• Viktor B. R. Pedersen and
• Mogens Brøndsted Nielsen

Beilstein J. Org. Chem. 2024, 20, 59–73, doi:10.3762/bjoc.20.8

• Sciences, Beijing, China 10.3762/bjoc.20.8 Abstract Large donor–acceptor scaffolds derived from polycyclic aromatic hydrocarbons (PAHs) with tunable HOMO and LUMO energies are important for several applications, such as organic photovoltaics. Here, we present a large selection of PAHs based on central

• acetylenic scaffolds comprised of enediyne units are known to behave as good electron acceptors [15][16], and we became interested in combining the IF-DTF scaffold with such motifs to generate novel multi-redox systems. For example, the radiaannulene moiety RA shown in Figure 1 (or its truncated counterpart

• easily degrade, which made their characterization somewhat difficult (vide infra). We also targeted other enediyne acetylenic scaffolds with IF as central core as shown in Scheme 5. Starting from IF dione 1, compounds 24 and 25 were synthesized via Ramirez/Corey–Fuchs dibromo-olefinations. Four-fold

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• polarizability [9][10][11], the dream scaffolds for induced anion–π interactions are carbon allotropes. Anionic transition states placed on C60 fullerenes 1 will drive the 60 π electrons toward the other side, thus inducing a transient macrodipole that will stabilize the same transition state that induced its

• ][86][87][88][89][90][91][92][93][94]. They serve as catch-and-release scaffolds in different variations, and, less frequently, as (photo)redox partners. Although they might contribute to these activities, anion–π interactions have not been considered. Anion–π catalysis on carbon nanotubes has been

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

• construction of these scaffolds [28][29][30][31], and one of the most efficient approaches is the cascade cyclization strategy [29][30][31]. Xu, Li, Wei and their co-workers successfully devised a series of highly regioselective iodide/phosphine synergistically catalyzed photocatalytic cascade annulations for

Quinoxaline derivatives as attractive electron-transporting materials

• Zeeshan Abid,
• Liaqat Ali,
• Sughra Gulzar,
• Faiza Wahad,
• Raja Shahid Ashraf and
• Christian B. Nielsen

Beilstein J. Org. Chem. 2023, 19, 1694–1712, doi:10.3762/bjoc.19.124

• materials further enhances the practicality and commercial viability of Qxs for charge transport applications [6][7][8][9][10]. Figure 1 shows a few Qx scaffolds used in development of Qx derivatives. The utilization of Qxs as a charge transporting material, whether as a hole transport material (HTM) or an

• vital role in shaping the next generation of electronic devices and renewable energy systems. Structures of some of the most versatile Qx scaffolds; dashed lines indicate the substitution sites for core expansion. Qx-derived polymer acceptors. Qx-derived small molecule NFAs. Qx-derived small molecule

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• scaffolds. α-Substituted amino acids, such as 2-aminoisobutyric acid, could be used to block the second cycloaddition. Shown in Scheme 12 is a method development for the stepwise synthesis of triazolobenzodiazepines. The reaction of 2-azidobenzaldehyde, 2-aminoisobutyric acid and N-ethylmaleimide in MeCN

•  6) [75]. One-pot double annulations for the synthesis of tetrahydropyrrolothiazoles The unique tetrahydropyrrolothiazole and spiro[indole-tetrahydropyrrolothiazole] scaffolds are found in bioactive compounds such as those shown in Figure 7 [76][77]. Using cysteine as a key reactant, we developed a

A series of perylene diimide cathode interlayer materials for green solvent processing in conventional organic photovoltaics

• Kathryn M. Wolfe,
• Shahidul Alam,
• Eva German,
• Fahad N. Alduayji,
• Maryam Alqurashi,
• Frédéric Laquai and
• Gregory C. Welch

Beilstein J. Org. Chem. 2023, 19, 1620–1629, doi:10.3762/bjoc.19.119

• the previously reported N-annulated PDI (PDIN-H) and nitrile functionalized N-annulated PDI (CN-PDIN-H) compounds (Figure 1c) as the scaffolds for modification [18]. The PDIN-H scaffold was modified by N-functionalization with a benzyl (PDIN-B) or pentafluorobenzyl group (PDIN-FB). Similarly, the CN

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

• these scaffolds, even though they are found within a number of biologically active alkaloids. We recently demonstrated that the readily available, bench-stable tricarbonyl(tropone)iron complex [4] (1, Scheme 1) could serve as a precursor to the previously unreported 2-azatricyclo[4.3.2.04,9]undecane

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• scaffolds is the introduction of a benzylidene moiety on C5 via a Knoevenagel reaction. Here, a facile synthesis of 5-arylidenerhodanines via a Knoevenagel reaction in an ʟ-proline-based deep eutectic solvent (DES) is reported. This method is fast (1 h at 60 °C), easy, catalyst-free and sustainable as no

• classes of heterocyclic compounds studied for a long time. Those scaffolds have attracted great attention since the introduction of various glitazones and epalrestat into clinical use for the treatment of type-II diabetes (Figure 1). Indeed, those compounds are often identified as hits in high throughput

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

• pharmaceutical molecules. Considering the synthetic applications of sulfur-based compounds, a large number of researchers have noted that these scaffolds have promising potential for the research and development of new biomedicines. In the sulfenylation of organic compounds, the sulfenylating agents are

• intermediate led to intramolecular cyclization. In 2020, electrophilic cyclization of allylic amides 134 using N-(phenylthio)succinimide 1 in the presence of camphorsulfonic acid (CSA) as a Brønsted acid and tetrabutylammonium chloride (TBAC) led to 5-[(phenylthio)methyl]oxazoline scaffolds 135 (Scheme 57) [89

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• organic synthesis to build complex scaffolds starting from simple starting materials. The Enders three-component cascade reaction was a cornerstone in the field and a plethora of organocatalyzed cascade reactions followed. However, acetaldehyde was not shown as a successful reaction partner, probably

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction

• Ziying Xiao,
• Fengshun Xu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1234–1242, doi:10.3762/bjoc.19.91

• indicated that only one diastereoisomer was predominately produced in the reaction, while the other possible diastereomers were not detected. This result shows that this reaction has a high diastereoselectivity due to the large steric effect of two oxindole scaffolds and the thermodynamically controlling

• effect. The single crystal structure of compound 3a was determined by X-ray crystallographic diffraction (Figure 1). From Figure 1 it can be seen that the two scaffolds of oxindole at neighboring positions are in trans-configuration. The ethoxycarbonyl group is also in trans-position to the carbonyl

• different reactivity to that of the adducts of 3-ethoxycarbonylmethyleneoxindoles. For confirming the chemical structures of dispirooxindoles 4a–i, the single crystal structure of compound 4a was determined by X-ray diffraction (Figure 2). In Figure 2, the two oxindole scaffolds are in trans-position. The

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

• addition to alkenes and radical decarboxylation, with many of these being driven by light energy. RLT in alkene functionalization Outside of the realm of C–H activation, RLT has been leveraged to afford complex medicinal scaffolds in alkene difunctionalization. A recent example can be found in the merger

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

• ; multicomponent synthesis; one-pot reaction; trichloroacetic acid; Introduction π-Conjugated porphyrin macrocycles are known for their applications in numerous areas ranging from oxygen transport, photosynthesis, catalysis and medicine [1][2][3]. In the past several years, diverse organic scaffolds have been

• contruction of periphery-modified porphyrinoids [30][31][32][33][34][35][36][37][38][39][40][41], we thought to assemble benzo[f]chromeno[2,3-h]quinoxalinoporphyrins by incorporating porphyrin, quinoxaline and xanthene scaffolds in a single molecular framework using a multicomponent synthetic strategy. The

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• indoline scaffolds (22a,b) via a radical-polar crossover mechanism (Figure 12C) [65], showcasing the power of conPET in dearomatization reactions. Finally, the synthesis of tetraphenylphosphonium chloride (20a) could be scaled up efficiently in an operationally very simple continuous-flow setup with only

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• ketimines 49 to construct an aza-quaternary stereocenter at the C3 position of oxindole scaffolds 61 bearing a β-naphtholyl substituent (Scheme 16b) [44]. In 2020, Meng, Chan, Zhao and co-workers reported another C3-selective aza-Friedel–Crafts reaction of 4-aminoindole derivatives 63 utilizing N-Boc-α

• than with indole (Scheme 19) [47]. In 2021, Zhang and co-workers used 5-aminoisoxazole scaffolds 82 in an enantioefficient aza-Friedel–Crafts reaction with isatin-derived N-Boc ketimines 49. A 2-oxindole-substituted aza-quaternary stereocenter was installed at the C4 position of the heteroaromatic ring

• -derived ketimines 49 was reported by Vila, Pedro and co-workers. Regioisomeric hydroxyquinolines were tested in this reaction to facilitate the electrophilic aromatic substitution on the ortho-carbon atom with respect to the hydroxy group in quinolines 15. The reaction affords oxindole scaffolds 116 with

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• obtained by other conjugate addition reactions. Keywords: acylimidazole; asymmetric catalysis; carbocation; conjugate addition; enolate; Introduction Asymmetric metal-catalyzed conjugate additions provide access to numerous chiral scaffolds. This type of C–C bond formation efficiently enables the