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

• aldehyde [10]. Latterly, Yamamoto utilized a 90% deuterated [D2]-isocyanide in a copper catalyzed [3 + 2] cycloaddition to afford a 60% deuterated [D2]-pyrrole [11]. The utility of the Leuckart–Wallach reaction towards the generation of isocyanides was first explored by Dömling [12], yet the use of such

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• pyrazoles. The review will primarily focus on two major categories: two-carbon and three-carbon building blocks as key intermediates, while other special cases will be summarized separately. Review (3 + 2)-Cyclocondensation – C3-building blocks as key intermediates The majority of the numerous pyrazole

• give 1,5-diacyl-5-hydroxypyrazolines 131. Cleavage of the protecting group with potassium carbonate in methanol finally provides the corresponding 5-acyl NH-pyrazoles 132 (Scheme 46) [149]. A novel approach to synthesizing pyrazoles via the initial formation of isoxazoles 138 through (3 + 2

• with electrophiles, such as deuteration or electrophilic chlorination using N-chlorosuccinimide, in this consecutive three-component synthesis to give persubstituted pyrazoles 165 (Scheme 55) [162]. (3 + 2)-Cycloaddition – C2 building blocks as substrates 1,3-Dipolar cycloadditions are important

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

• agrochemical industries. The (3 + 2)-cycloaddition between nitrile imines and alkenes represents one of the most efficient strategies to prepare these azacycles. However, conventional methods for the generation of the nitrile imine involved the use of unstable hydrazonoyl halides or the oxidation of aldehyde

• -derived hydrazones under harsh reaction conditions. In 2023, the group of Waldvogel presented a formal electrooxidative (3 + 2)-cycloaddition between aldehyde-derived hydrazones 72 and alkenes 73 to yield a large range of N-arylpyrazolines 74 under mild reaction conditions (Scheme 14) [58]. A biphasic

• situ cathodic generation of the base was supported by a control experiment in a divided cell, where no conversion was achieved. Final formal (3 + 2)-cycloaddition with the dipolarophiles 73 delivered the pyrazolines 74. It is interesting to note that a complementary (3 + 2)-cycloaddition between

Radical reactivity of antiaromatic Ni(II) norcorroles with azo radical initiators

• Siham Asyiqin Shafie,
• Ryo Nozawa,
• Hideaki Takano and
• Hiroshi Shinokubo

Beilstein J. Org. Chem. 2024, 20, 1967–1972, doi:10.3762/bjoc.20.172

• the electrophile [16][17][18]. In addition, C–C double bonds of the norcorrole skeleton outside the π-delocalization pathway exhibit a reactivity similar to an alkene to afford hydrogenated norcorroles by hydrogenation [19] or reduction with hydrazine [20] and [3 + 2]-cycloadducts with 1,3-dipoles [21

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

• )-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

• activity. 2-Aminoethylthiophene derivatives with therapeutic activity, part 1. 2-Aminoethylthiophene derivatives with therapeutic activity, part 2. 2-Aminoethylthiophene derivatives with therapeutic activity, part 3. 2-Aminoethylpyrrole derivatives with therapeutic activity. Histamine metabolic pathway. 2

• -Aminoethylimidazole derivatives with therapeutic activity, part 1. Krel is referred as histamine relative potency (basal reference 1.0). Conformationally restricted 2-aminoethylimidazole derivatives with therapeutic activity, part 2. 2-Aminoethylimidazole derivatives with therapeutic activity, part 3. 2

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

• a [1,5]-H shift [19], indazolo[3’,2’:2,3]imidazo[1,5-c]quinazolin-6(5H)-one 18 (Scheme 7) [20]. The favorable host–guest interaction between 14 and the reactants (demonstrated by 2D NMR and FTIR spectroscopy as well as by scanning electron micrography), combined with the acidity of the succinyl

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• , and different convertible isocyanides gives rise to products of the classic Ugi reaction, ethyl (E)-4-(4-(R1-amino)-1-chloro-3-(2-chloro-N-(4-(R2)phenyl)acetamido)-4-oxobut-1-en-1-yl)-3,5-dimethyl-1H-pyrrole-2-carboxylates, which, however, exhibit unusual behavior in post-Ugi transformations. The

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

• of these compounds via an intramolecular [3 + 2] cycloaddition reaction between (Z)-steroidal arylidene derivatives 42 and azomethine ylides (Scheme 13) [26]. The latter were generated in situ from sarcosine (MeNHCH2CO2H) and a mono- or dicarbonyl compound such as isatin, acenaphthenequinone, and

• 82 with concentrated sulfuric acid, cyclodehydration occurred, leading to the formation of 3-spiro[3’’’-(2’’’-phenyl-4’’’-oxo-1’’’,3’’’-thiazolidin-5’’-yl)-1’’,3’’,4’’-thiadiazolo[3’,4’-b]thiazolin]cholest-5-ene (83) in 60% yield (Scheme 24). Notably, stereochemical information at the newly formed

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

• ., 3-aminopyrazole (1{1}), 3-aminoisoxazole (1{2}), 2-aminothiazole (1{3}), 2-amino-1,3,4-thiadiazole (1{4}), or 2-aminotetrazole (1{5}) demonstrated poor conversion to the target products; 2-aminopyrimidines either gave isomeric mixtures (e.g., parent compound 1{6}, alkyl-substituted derivatives 1{7

• experience, 4-fluoro- and 4-chloro-2-fluoro-1-isocyanobenzenes (3{1} and 3{2}) showed poor performance and unsatisfactory results were also observed for isocyanocyclopropane (3{3}). Using the guidelines described above, we have updated the reactant lists with additional representatives and excluded those

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• ), catalyst B2 (10 mol % related to 1), and Cs2CO3 (3 equiv). Then the respective allenoate 3 (2 equiv) and toluene (0.05 M with respect to 1) were added and the mixture was stirred at room temperature for 24 h (Ar atmosphere). The crude product was passed through a short column of silicagel (rinsed with DCM

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

• -3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity. The reaction was finished by in situ generation of activated 5-(alkylimino)cyclopenta-1,3-dienes from addition of alkyl isocyanide to two molecules of but-2-ynedioates and sequential formal [3 + 2] cycloaddition

• 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

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• , such as 6a. These studies include various types of chromones, including 2,3-unsubstituted chromone (9a), 3-formylchromone (10a), 3-acetylchromone, 3-(methoxalyl)chromone (11a), 3-benzoylchromone (12a), 3-(2-nitrobenzoyl)chromone (13a), 3-trifluoroacetylchromone (14a), 3-perfluoroalkanoylchromones, 3

• yields (up to 74%) were obtained for products containing nitro groups. 3-(2-Nitrobenzoyl)chromones Dimethyl acetone-1,3-dicarboxylate A completely different result was obtained when chromones containing a 2-nitrobenzoyl group were employed. The reaction of dimethyl acetone-1,3-dicarboxylate (3) with 3-(2

• a 2-fluorophenyl group, the regioselectivity was different and product 26 was obtained (see Scheme 12). The yields were, in general, very good. The best yield (84%) was obtained for the reaction of 6-methyl-substituted 3-(2-nitrobenzoyl)chromone 13b, presumably due to a better solubility of the

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• racemisation, and nucleoside 14 with the same α/β ratio of 3:2 formed from either anomerically pure 17 or from a mixture of the anomers. Catalytic hydrogenation is usually used for the removal of benzyl protecting groups. However, standard hydrogenation conditions using 10% Pd/C led to reduction of the C=C

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• indolo[1,2-c]quinazolin-6(5H)-one derivatives. Finally, starting from 1,2-bis(2-nitrophenyl)ethene and 1-methoxy-2-nitro-3-(2-nitrostyryl)benzene the related indolo[3,2-b]indoles were not observed (Scheme 17). One year later, by using continuous flow technology, Gutmann, Kappe and colleagues developed 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

• tetrasubstituted BCHs was recently reported by Shi and co-workers [82]. They employed Hantzsch esters as catalysts in the [2π + 2σ] cycloaddition of alkenes and bicyclobutanes. The synthesis of bicyclohexyl ketones by formal (3 + 2) cycloaddition of bicyclobutane and ketenes was recently reported by Studer and co

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• out. In this case, a mixture of 2-chloro-1,1,1,4,4,4-hexafluorobut-2-enes (6a,b) and 2-iodo-1,1,1,4,4,4-hexafluorobut-2-enes (7a,b) in a ratio of 3:2 was formed from the concurrent elimination reactions of hydrogen iodide and hydrogen chloride (Scheme 5). The chloro- and iodobutenes were separated by

• and previously unknown product 11 were also recorded in the reaction mixture (Scheme 7). The 19F NMR spectrum of compound 11 showed two signals at −65.6 and −99.1 ppm in a ratio of 3:2 and in the 1H NMR spectrum, a multiplet at 6.5 ppm was detected. Based on the received data, we assumed that product

• of allene resulted in the formation of (Z)-1,2-dibromo-1,1,4,4,4-pentafluorobut-2-ene (13) in 92% yield, which was isolated as a colorless liquid and fully characterized by NMR spectroscopy (Scheme 10). The 19F NMR spectrum showed two signals with the integrated intensity ratio 3:2, a doublet for a

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• ketimines as suitable three-carbon synthons in [3 + 2] and [3 + 3] annulations [11][12][13][14][15]. However, methods using N-sulfonyl ketimines as dienophiles in [4 + 2] annulation reactions to afford biologically important spiro compounds are still limited to date [16]. 1,2-Diaza-1,3-dienes [17][18][19

Catalytic multi-step domino and one-pot reactions

• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2024, 20, 254–256, doi:10.3762/bjoc.20.25

• . Zhang, Ma, and W. Zhang reflects the state of the art in the α-amino acid-based [3 + 2] cycloaddition reactions of N–H-type azomethine ylides in multicomponent, one-pot, and stepwise reactions for the synthesis of diverse bioactive heterocyclic compounds and natural products [9]. Computational studies

Synthesis of the 3’-O-sulfated TF antigen with a TEG-N₃ linker for glycodendrimersomes preparation to study lectin binding

• Mark Reihill,
• Hanyue Ma,
• Dennis Bengtsson and
• Stefan Oscarson

Beilstein J. Org. Chem. 2024, 20, 173–180, doi:10.3762/bjoc.20.17

• Celite® and concentrated in vacuo. The resulting residue was taken up in EtOAc (700 mL) and washed with 10% aq Na2S2O3 (700 mL), water (700 mL) and brine (700 mL). The organic phase was then dried over MgSO4, filtered and reduced to dryness. Flash chromatography on silica gel (toluene→toluene/EtOAc, 3:2

• concentrated under reduced pressure. Flash chromatography on silica gel (toluene→toluene/acetone, 7:3) yielded 5 as a gold-coloured syrup (7.83 g, 96%). Rf = 0.4 (toluene/EtOAc, 3:2); [α]D +67 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.58 (d, J = 9.8 Hz, 1H, NH), 4.93 (d, J = 3.6 Hz, 1H, H-1), 4.77 (d, J

• )ethoxy]ethyl 2,3,4,6-tetra-O-acetyl-β-ᴅ-galactopyranosyl-(1→3)-2-deoxy-4,6-O-di-tert-butylsilylene-2-(2’2’2’-trichloroethoxycarbonylamino)-α-ᴅ-galactopyranoside (7): Donor 6 [16] (7.67 g, 17.4 mmol) and acceptor 5 (7.57 g, 11.6 mmol) were placed under N2 together and dissolved in dry CH2Cl2 (230 mL). AW

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• reactions, yielding multicyanated ethenes [95]. Contrarily, alkenes bearing three or four ester substitutions partake in a [4 + 2]-type hetero-Diels–Alder (DA) reaction, yielding a third product, presumably through a [3 + 2] cycloaddition reaction, followed by rearrangement. The [2 + 2] CA–RE reactions

• equivalents of TCNEO relative to the alkyne substrate for the generation of the TCBD products [100]. For the reaction, the formal [3 + 2] cycloaddition reaction is postulated to initiate through the initial nucleophilic attack of the alkyne carbon on the electrophilic TCNEO carbon, yielding a zwitterionic

Aldiminium and 1,2,3-triazolium dithiocarboxylate zwitterions derived from cyclic (alkyl)(amino) and mesoionic carbenes

• Nedra Touj,
• François Mazars,
• Guillermo Zaragoza and
• Lionel Delaude

Beilstein J. Org. Chem. 2023, 19, 1947–1956, doi:10.3762/bjoc.19.145

• system (G) was first investigated by Albrecht et al. in 2008 [23]. Because the heterocyclic precursors needed to prepare 1,2,3-triazol-5-ylidenes are readily available through the [3 + 2] cycloaddition of an azide and an alkyne, these compounds are currently the most popular MICs for catalytic and other

• -disubstituted-1,2,3-triazole derivatives is readily achieved via the copper(I)-catalyzed [3 + 2] cycloaddition of an azide and a terminal alkyne (CuAAC) [63][64][65]. A further alkylation of the N3 position with an alkyl halide is an equally straightforward procedure that ultimately affords a large assortment

Construction of diazepine-containing spiroindolines via annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates

• Xing Liu,
• Wenjing Shi,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1923–1932, doi:10.3762/bjoc.19.143

• spirooxindoles [36][37][38][39][40][41][42][43]. In the presence of Lewis bases, isatin-derived MBH carbonates usually undergo [3 + 2] and [3 + 3] cycloaddition reactions with a broad range of active C–C and C–N double bonds and 1,3-dipolarpohiles to give various five- or six-membered cyclic spirooxindoles [44

Beyond n-dopants for organic semiconductors: use of bibenzo[d]imidazoles in UV-promoted dehalogenation reactions of organic halides

• Kan Tang,
• Megan R. Brown,
• Chad Risko,
• Melissa K. Gish,
• Garry Rumbles,
• Phuc H. Pham,
• Oana R. Luca,
• Stephen Barlow and
• Seth R. Marder

Beilstein J. Org. Chem. 2023, 19, 1912–1922, doi:10.3762/bjoc.19.142

• been used by Murphy’s group and others for a variety of transformations, such as the formation of indolines from N-allyl-2-iodoanilines [1], indanones from 3-(2-halophenyl)propanoic esters [2][3], and 3-methyl-2,3-dihydrobenzofuran from 1-allyloxy-2-halobenzenes [4]. Related species have also been used

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

• notable advantages in terms of both step- and atom-economy. Taking inspiration from the groundbreaking work of Shang and Fu [6], Li and colleagues demonstrated an innovative approach for the photocatalytic [3 + 2] and [4 + 2] annulation of enynals 32 and γ,σ-unsaturated N-(acyloxy)phthalimides 33 (Scheme

• of fused ketones 34, eliminating the need for transition-metal catalysts or oxidants. The technique offered a broad substrate scope, remarkable selectivity, and simple reaction conditions. A plausible mechanism had been proposed for the photocatalytic decarboxylative [3 + 2]/[4 + 2] annulation, as

• alkylation employing ammonium iodide. NaI/PPh3/CuBr cooperative catalysis for photocatalytic C(sp3)–O/N cross-coupling reactions. Proposed mechanism of NaI/PPh3/CuBr cooperative catalysis for photocatalytic C(sp3)–O/N cross-couplings. Photocatalytic decarboxylative [3 + 2]/[4 + 2] annulation between enynals