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

• mechanism is as follows: pyridine deprotonates tetrachloro-N-hydroxyphthalimide (R2N–OH), which is subsequently anodically oxidized. The resulting N-oxyl radical abstracts a hydrogen atom from the position adjacent to the olefin, forming an allylic radical. This allylic radical then reacts with cathodically

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• -triazole, thiazole, or pyridine were synthesized by the reaction of 3,5-di-tert-butyl-o-benzoquinone or 3,5-di-tert-butyl-6-methoxymethylcatechol with different heterocyclic thiols. The S-functionalized catechols were prepared by the Michael reaction from 3,5-di-tert-butyl-o-benzoquinone and the

• -derivatives of thiazole or pyridine, this process leads to the formation of the corresponding thioethers with a methylene linker. At the same time, thiolated 1,3,4-oxadiazole or 1,2,4-triazole undergo alkylation at the nitrogen atom in the reaction with 3,5-di-tert-butyl-6-methoxymethylcatechol to form the

• view of studying their potential biological activity. This work aimed to obtain new multifunctional catechols containing pharmacologically active heterocyclic fragments such as thiazole, 1,3,4-oxadiazole, 1,2,4-triazole, and pyridine. We decided to use a non-hydrolyzable thioether group as a bridging

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

• diastereomeric mixtures with comparable yields of 38% (1.0:2.0 trans/cis, from cis-1n) and 35% (1.7:1.0 trans/cis, from trans-1n). Olefins containing N-heteroaromatics such as phthalimide and pyridine underwent aziridination to give 3o (32% yield) and 3p (26% yield). Similarly, 1,4-cyclohexadiene was compatible

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• scrambling. GBB reaction products, no deuterium scrambling was observed. aA 70% [D2]-isocyanide was used in 7a and 7b. Ar = 4-PhPh, Ar1 = 4-MePh. Modified Hantzsch pyridine synthesis to afford 1,4-dihydropyridines. No deuterium scrambling was observed. CYP3A4 mediated dehydrogenation of dihydropyridines

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

• the use of HF or its complexes as a reagent. These reactions seem to proceed via the formation of the vinyl fluoride as the intermediate [25][26][27][28]. In the first example, Olah and co-workers reported the reaction of terminal alkynes with HF/pyridine (Olah reagent) (Figure 1, reaction 1) [29][30

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• synthesize tricyclic pyridine derivatives in a single step (Scheme 22) [75]. Zhang and Yu et al. also developed a cyclization of 2-isocyanobiaryls using a photoredox system [76][77][78][79][80] in which carbon radicals were generated by a photoredox reaction of α-bromopropanoates under visible light

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• the partner might be investigated offering numerous possibilities for the assembly of heterocycles. As early as 1988, Tabaković and Gunić examined the anodic oxidation of aldehyde-derived NH-arylhydrazones 44 in the presence of pyridine and (iso)quinolone derivatives 45 in acetonitrile

• pyridine, triphenylphosphine or tetraethylammonium cyanide, the corresponding pyridium 109, phosphonium 111 and cyano hydrazones 113 were obtained, respectively (Scheme 21) [69]. In 2020, Ruan and Sun et al. communicated the electrochemical dehydrogenative coupling between (hetero)aromatic or aliphatic

A new platform for the synthesis of diketopyrrolopyrrole derivatives via nucleophilic aromatic substitution reactions

• Vitor A. S. Almodovar and
• Augusto C. Tomé

Beilstein J. Org. Chem. 2024, 20, 1933–1939, doi:10.3762/bjoc.20.169

• excellent nucleophiles and generally react under mild conditions, resulting in the substitution of the 4-F atom of the pentafluorophenyl groups. In this case, reactions with thiols were performed in dry DMF and K2CO3 was used as the base. Three different thiols were tested: pyridine-4-thiol, pyridine-2

• -thiol and 4-(acetylamino)benzenethiol. The reaction with pyridine-4-thiol yielded a mixture of the di- and monosubstituted compounds 3a and 4a in 51% and 23% yields, respectively. Conversely, for the reaction with pyridine-2-thiol, exclusively produced the disubstituted compound 3b in an 85% yield

• contrast to the reaction with pyridine-4-thiol, which resulted in the S-substituted product 3a, the reaction with 4-hydroxypyridine led exclusively to the formation of the pyridin-4-one-derived compounds 3f and 4f, in 45% and 13% yield, respectively. The substitution occurred at the nitrogen atom rather

Novel oxidative routes to N-arylpyridoindazolium salts

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

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• -pyridine substituted diarylamines, either using bis(trifluoroacetoxy)iodobenzene as an oxidant, or electrochemically, via potentiostatic oxidation. Electrochemical synthesis occurs under mild conditions; no chemical reagents are required except electric current. Both approaches can be considered as a late

• organic synthesis. In the present paper, convenient, easily reproducible, straightforward synthetic routes to N-arylpyridoindazolium salts were elaborated, based on both electrochemical and chemical (using bis(trifluoroacetoxy)iodobenzene, PIFA) oxidation of the ortho-pyridine-substituted diarylamines

• . Voltammetry studies of the electrochemical behavior of the novel pyridoindazolium salts and the starting diarylamines were performed confirming a possibility for their reversible redox interconversion. Results and Discussion Chemical oxidation Three previously reported ortho-pyridine-substituted diarylamines

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• , commercial compound 1 (Scheme 2) represents a rescaffolding exercise to pyridine retaining low inhibitory activity although it was found toxic in in vitro assays on a human T-cell line and PBMCs (periferal blood mononuclear cells). The derivatives (R)-2 and (S)-2 were elaborated by Berger et al. [7] in the

• )-2, also called lanicemine, AZD6765 or AR-R15896AR, was described as a competitive ketamine alternative without psychotomimetic side effects, although potency and selectivity were significantly lower (Scheme 2) [8][9]. Dukat et al. [10] developed flexible 3-(2-aminoethyl)pyridine (AEP) analogs 3–5 as

• possibility of different binding topologies to the α4β2 receptor. Betahistine (6) is an orally active 2-(2-aminoethyl)pyridine drug indicated for vestibular disorders like Meniere’s disease, whose patients exhibit acute vertigo attacks (Scheme 2) [11][12]. Gbahou et al. [13] demonstrated histaminergic synapse

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• their reduced nucleophilicity. Also the synthesis of a bis-imidazo[1,2-a]pyridine scaffold was achieved in 43% yield from the pseudo-para-substituted bis-aldehyde, using the same conditions, but longer reactions times (6 days). Following the same approach, the authors also developed a one-pot protocol

• Ganesher [57] reported the one-pot cascade synthesis of indole-imidazo[1,2,a]pyridine hybrids 61 (Scheme 23). In this study, the convertible isocyanide 1-isocyano-2-(2,2-dimethoxyethyl)benzene (59, Kobayashi–Wessjohann isocyanide) was utilized as one of the precursors in the GBB reaction. The acetal

• comprising a GBB-3CR and a palladium-catalyzed azide-isocyanide coupling to generate imidazo[1,2-a]pyridine-fused 1,3-benzodiazepines 85 (Scheme 27). The GBB reaction smoothly proceeded using 2-azidobenzaldehydes 83, 2-aminopyridines and isocyanides as the precursors. The in situ-generated azides 84 were

Hetero-polycyclic aromatic systems: A data-driven investigation of structure–property relationships

• Sabyasachi Chakraborty,
• Eduardo Mayo Yanes and
• Renana Gershoni-Poranne

Beilstein J. Org. Chem. 2024, 20, 1817–1830, doi:10.3762/bjoc.20.160

• in size, composition, and aromatic character: benzene, pyridine, pyrazine, borinine, 1,4-diborinine, 1,4-dihydro-1,4-diborinine, borole, pyrrole, furan, thiophene, and cyclobutadiene (Figure 1A). These building blocks encompass 6-, 5-, and 4-membered rings with aromatic and antiaromatic character

• Information File 1. For the N-containing heterocycles, we observe a similar dichotomy, although in this case all systems are aromatic. The two six-membered rings (pyridine and pyrazine) shift the distribution to the left and downwards of the baseline, towards lower HOMO and LUMO values (the effect is more

• pronounced for pyrazine than pyridine). Conversely, the five-membered ring (pyrrole) shifts it to the right and upwards, maintaining a similar HOMO range to COMPAS-1, but extending into much higher LUMO values. The behavior of the various N-containing rings is well documented in the literature [17][44][45

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• bonding is well-established in hypervalent iodine(III) compounds and Dutton showed that pyridine formed a weak complex with dichloroiodobenzene via halogen bonding [30][31][32]. We therefore added dry pyridine (2.4 equivalents) to difluoroiodane 6 in CDCl3 to help stabilise the iodine(V) centre and the

• (blue line), dry CDCl3 with 2.4 equivalents of dry pyridine (green line), and dry CDCl3 (red line). Order of hydrolytic stability for the four hypervalent iodine(V) fluorides. Examples of fluorination using hypervalent iodine(III) reagents 1 and 2. Preparations and reactions of hypervalent iodine(V

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

• )-spiro[cholest-5-en-3,2’-[1,3,4]-oxadiazoline] (99) through the acylation of semicarbazone 98 using freshly distilled acetic anhydride and pyridine at 80 °C [55]. Semicarbazone 98 was initially obtained via condensation of cholest-5-en-3-one (97) with semicarbazide hydrochloride in a refluxing ethanol

• -cholest-8-en-3-one thiadiazoline 101 from thiosemicarbazone 100. This last compound was treated with acetic anhydride in refluxing pyridine, resulting in the formation of the desired product in 64% yield (Scheme 30). No information was given about the stereochemistry at C-3. More recently, steroidal mono

• -thiosemicarbazones 103 were still observed in minor quantities (6–11% yields). In both cases, thiosemicarbazones were obtained as a mixture of E and Z isomers, which were subsequently treated together with freshly distilled acetic anhydride and pyridine at 85 °C, yielding a single product (56–73% yield). The only

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

• , allowing the total synthesis of bisorbicillinol (37). Meanwhile, treatment of the resulting (S)-34 under harsher conditions, such as reflux in pyridine, resulted in a distinct intermolecular Diels–Alder reaction between the cyclohexadienone moiety and the side chain of (S)-34 enabling the first total

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• } and 1{8}) or showed low conversion (halogenated derivatives 1{9–11}); 4-aminopyrimidines 1{12–16} also demonstrated low conversion; pyridine derivatives with electron-withdrawing substituents (such as NO2 at C-3 or C-5 positions, as well as CN, SO2NH2, or C(O)NH2 at the C-3 atom) did not work

• (compounds 1{17–21}); for pyridazine or pyrazine derivatives, even the presence of halogen atoms was sufficient to deactivate the substrate (e.g., compounds 1{22–24}); a dialkylamino or alkoxy group at the C-6 position of pyridine derivatives also hampered the substrate’s reactivity (e.g., compounds 1{25–27

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• anilines were obtained. The quinoline reduction was efficiently promoted by adding a catalytic amount of p-toluenesulfonic acid (PTSA) or pyridinium p-toluenesulfonate (PPTS). Pyridine was also reduced to piperidine in the presence of PTSA. Keywords: cyanoarene; nitroarene; PEM reactor; pyridine

• synthesis. Therefore, the electroreduction of pyridine (8a) was performed (Table 6). First, the electroreduction of 8a was performed with 0.1 equiv of PTSA, and 1.0 equiv of PTSA was added after electrolysis to determine the yield by 1H NMR analysis (Table 6, entry 1). The yield of 9a·PTSA (26% yield) was

• contrast to quinolines, 4-methylpyridine (8e) gave 4-methylpiperidine (9e) in a moderate yield. 4-Phenylpyridine (8f) afforded a small amount of the target product 9f and 91% of 8f was recovered, probably because of steric hindrance of 8f. 2,6-Disubstituted pyridine such as 2,6-lutidine (8g) was also

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• Xiu-Yu Chen Ying Han Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Jiangsu, Yangzhou 225002, China 10.3762/bjoc.20.126 Abstract An efficient protocol for the synthesis of polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H

• )-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine

• reaction with 5,6-unsubstituted 1,4-dihydropyridine. Keywords: [3 + 2] cycloaddition; cyclopenta-1,3-diene; cyclopenta[4,5]pyrrolo[2,3-b]pyridine; 1,4-dihydropyridine; electron-deficient alkyne; isocyanide; Introduction Isocyanide is a unique and attractive functional group in organic chemistry. The

A comparison of structure, bonding and non-covalent interactions of aryl halide and diarylhalonium halogen-bond donors

• Nicole Javaly,
• Theresa M. McCormick and
• David R. Stuart

Beilstein J. Org. Chem. 2024, 20, 1428–1435, doi:10.3762/bjoc.20.125

• halogen-bond interaction of diarylhalonium salts with pyridine decreased with increasing s-character used by the central halogen atom in the bond opposite the halogen bond; this is effectively the s-character in the σ*-orbital [21]. Conceptually, halogen-bond donors are commonly described by the

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• , THF/pyridine (9:1), −20 °C to 21 °C, 12 h, b) Cs2CO3, DMSO, 120 °C, 2–3 d, c) TFA, TMS-N3, DCM, 25 °C, 12 h, d) 1. TFA, TMS-N3, DCM, 0–50 °C, 12 h; 2. alkyne, THF/H2O, CuSO4, sodium ascorbate, 16 h, 50 °C. Synthesis of triazenylpyrazoles 15a–d and functionalization to N-substituted triazenylpyrazoles

• 17a–r and 18a–r. Conditions i: 1) BF3·OEt2, isoamyl nitrite, THF, −20 °C, 1 h, 2) diisopropylamine, THF/pyridine/acetonitrile, −20 °C to 21 °C, 17 h; Conditions ii: 1) HClaq (6 M), NaNO2, 0 °C to 5 °C, 1–2 h, 2) diisopropylamine, 0 °C to 21 °C, 16 h. X = F, Br, I. Supporting Information The

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• borylation of tertiary alcohols using oxalates as a radical source and Ir(ppy)3 as a photocatalyst (Scheme 12). At first, the tertiary alcohols were functionalized using Barton pyridine-2-thione-N-oxycarbonyl (PTOC) esters for tert-alkyl radical generation. Next, the oxalates were utilized for borylation in

• PhSO2H and a pyridine species, thereby completing the catalytic cycle. Direct C–O bond activation of alcohols Alcohols have a high C–O bond strength and redox potential, making it difficult to directly activate the C–O bonds and produce carbon-centered radicals. Thus, to generate carbon-centered radicals

• -based activator. The deoxyalkylation was performed by initially stirring the alcohol substrate with NHC and pyridine in MTBE for 15 min. After that, Michael acceptor, sodium acetate, 1,1,3,3-tetramethylguanidine, and [Ir(III)] photocatalyst in MTBE/DMA were added to the mixture. Then, blue LEDs were

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• 3pa and 3qa, respectively. In addition to the successful transformations of heteroaryl iodides with indole or pyridine cores (3ra, 3sa), the electroreductive synthesis of methaqualone derivatives was also achieved (3ta). Pleasingly, a series of electron-deficient alkene and styrene derivatives were

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• conventional Diels–Alder reactions [95][118][119][120][121][122][123][124]. On the other hand, the initially exo carboxylic acid substituent in the oxanorbornene ring is converted to its endo isomer by epimerization upon heating the cycloadduct in a mixture of pyridine–glacial acetic acid (1:1). In the process

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• position (ortho or para) available for electrophilic substitution [36]. They found that solvent played a significant role in directing the outcome of the reaction. In protic solvents, biphenols were selectively formed through C–C bond formation, whereas in pyridine, the generation of diaryl selenide

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• , 72, 74 and 84% yield, respectively. An exception was noticed for N-heterocycle units (pyridine and 1H-pyrrole) substituted in the same position, since compounds 8g, 8l and 8i were obtained in 56, 51 and 36% yield, respectively. The 1,2,3-triazole hybrid isatin compound 8n was obtained in 56% yield