Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• interrupted CuAAC mechanism [65]. The thiotriazole product of this reaction, which is indistinguishable in the protein-level downstream analysis, is formed by coupling between protein free thiol groups and the triazole–copper adduct (Figure 4). However, its formation can be avoided by eliminating the free

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• center in proximity to the reactive moiety of the covalent substrate adduct to the catalyst contributes to the efficient transfer of chirality to the resulting product, even in the distant position of the 1,6-conjugated system [39]. For these reasons, iminium catalysis using primary amines appears to be

• product with 93% ee after 24 h, while the bifunctional primary amine-thiourea catalysts (system B) required 4 days to provide an adduct with similar enantioselectivity. Prolonged reaction time is in general the innate nature of organocatalytic reactions employing iminium activation approaches. With the

• impressive boost of the reaction rate in the ball mill was observed (3 h vs 4 days), the stereochemical outcome suffered giving the desired adduct with 59% ee instead of 94% ee in solution. Owing to the introduction of an additional functional group in the form of a thiourea moiety does not entail a

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• indicates that the formed double azide adduct is 6a, which is consistent with our previous report [18]. The double azide addition was further investigated by changing the reaction temperature. The rate constant was determined by the temperature-dependent 1H NMR spectra in CDCl3. The reaction kinetics

• outer side (in-out-ts), but the thermodynamically stable final product is a regioselective “in-in” adduct, i.e., compound 6a. Optical properties Absorption and emission spectra of 6a were measured in CH2Cl2 (Figure 5). The conjugation is changed and a highly-twisted macrocyle forms by the double azide

• were almost independent of solvents. For example, the λem in CHCl3 and THF was 514 nm (Figure S11 in Supporting Information File 1). The double benzyl azide adduct of DBA-OHex displayed similar absorption and emission spectra with a λmax of 247 nm and λem of 539 nm in CH2Cl2. Since the Stokes shift of

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• form adduct I', which is then transformed into intermediate II' by elimination of ethanethiolate. Subsequently, β-keto amide 3a is obtained when II' releases H+. Conclusion In summary, we have successfully developed an environmentally friendly method for the selective aqueous synthesis of β-keto

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

• -Addition of molecular bromine to phenyl isocyanide was reported by E. Kühle et al. to afford the corresponding 1,1-adduct (PhN=CBr2) [23]. Since dichloro compounds (RN=CCl2) [24] are the imino derivatives of highly toxic phosgene (O=CCl2), reactions using them as key intermediates are not safe synthetic

• ]. In the case of aromatic isocyanides, the 1,1-addition reaction is probably more likely to proceed because the C–N double bond of the 1,1-addition product 4 (R = Ar, E = PhS) is conjugated to the aromatic ring, which stabilizes it compared to the corresponding adduct with aliphatic isocyanides

• to give the corresponding 1,1-adduct (Et2P–C(=NPh)–GeEt3, 13) in 46% yield [40]. Similarly, Me2N-SnMe3 was known to add to p-tolyl isocyanide to give Me2N–C(=N–C6H4–p-Me)–SnMe3 (14) in good yield [41]. However, the authors did not specify whether the addition reactions proceeded by a radical or ionic

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• 1h–j proved also efficient for this rearrangement giving rise to the corresponding thioethers 2h–j in good NMR yields and lower isolated yield in the case of the more volatile adduct 2i. Finally, trifluoromethyl selenoxide 1k was tested as a substrate, and the rearranged product was obtained in a low

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

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• in most cases. A triple Michael adduct, tetrahydrochromen-4-one, is also formed as a side product in a few cases with excellent diastereoselectivity. Keywords: arylidenemalonates; curcumins; cyclohexanones; diastereoselective synthesis; Michael reaction; tetrahydrochromenones; Introduction There is

• to the increase in electron density at the carbon β to the ester group thus inhibiting the Michael addition of curcumin (Table 2, entry 4). Arylidenemalonate 2e, bearing a weakly electron-donating substituent, reacted with 1a to afford the double Michael adduct 3e in moderate yield (46%), and the

• triple Michael adduct 4e was not detected (Table 2, entry 5). Bulky 1-naphthyl analog 2f delivered the double Michael adduct 3f as the only product in a very good yield (73%, Table 2, entry 6). Heteroarylidenemalonate 2g also reacted well with 1a, affording 3g in 54% yield (Table 2, entry 7

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

• absence of an electrical current, thus allowing the addition of in situ-generated HCN to the hydrazone 155. After addition of a second equivalent of sodium cyanide, the resulting HCN adduct 156 was electrolyzed under constant current to form diazene 157, which subsequently underwent addition of methanol

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

• benzoyl peroxide, TEMPO, and the combination of alkyl halides with BEt3, were not applicable to this reaction. Physical properties The electronic absorption spectra of norcorrole 1 and adduct 2a are shown in Figure 3. While norcorrole 1 exhibited a weak absorption band from 600 nm to the NIR region, due

1,2-Difluoroethylene (HFO-1132): synthesis and chemistry

• Liubov V. Sokolenko,
• Taras M. Sokolenko and
• Yurii L. Yagupolskii

Beilstein J. Org. Chem. 2024, 20, 1955–1966, doi:10.3762/bjoc.20.171

• reacted with hexachlorocyclopentadiene at 200–220 °C within 3–4 days, forming 5,6-endo,endo-difluoro-1,2,3,4,7,7-hexachlorobicyclo[2.2.1]-2-heptene (Scheme 20) in 66% yield. At the same time, (E)-1,2-difluoroethylene, which formed the endo,exo-adduct, reacted much slower, and completion of the reaction

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

• conditions were tried in a GBB reaction, no cooperative effect was observed, but even a slight decrease in catalytic activity. The use of thiamine hydrochloride as organic catalyst was reported by Yamajala et al., who were able to obtain the GBB adduct depicted in Scheme 2 (3, R = t-Bu) in 97% under solvent

• the addition of tert-butyl isocyanide. On the other hand, the addition of tert-butyl isocyanide on the imine altered the orientation of adduct 19, suppressing the interaction with Ser105 (Scheme 8). Very recently, Tyagi et al. reported the double encapsulation of CALB and Pd(PPh3)4 within silica

• adduct in more than 4 grams in a total time of 8 hours. The same amount was obtained in batch in a total time of 20 hours. 2 Novel building blocks The scope and limitations of the GBB-3CR have been accurately delineated up to 2018, outlining a comprehensive understanding of its development, observing

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• via Knoevenagel adduct formation as a first step, which may become a significant limitation of this reaction. However, we have never observed and isolated Knoevenagel adducts of aromatic aldehydes 4 and N,N-dimethylbarbituric acid (5) during the synthesis of 5-aryldeazaalloxazines 2a–x in either of

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine has allowed the use of these compounds in the Ugi reaction without triggering competitive reactions. The additional functional group present in the resulting Ugi adduct can be leveraged in different post-condensation

• chromatography column, while the more eco-friendly second strategy needs an additional stage for the reduction of the nitro group on the Ugi adduct. In order to find a more efficient synthesis, we thought that the second nitrogen in the diazepine nucleus could be incorporated without the need of surrogates or

• workup the only product observed was the corresponding benzodiazepinone 5, resulting from a spontaneous cyclization of the Ugi adduct, in a six-center four-component Ugi reaction (U-6C-4CR), which prevents the need of additional steps (Scheme 1, Table 1). Due to the interest of these results and

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

• steroidal 17-ketones were first alkylated in the presence of the lithium derivative of ethyl propiolate. After stereoselective formation of the corresponding adduct, the triple bond was chemoselectively reduced under catalytic hydrogenation using 5% palladium on charcoal. As a final step, a p

• revealed that the adduct occupies the same position as the endogenous ligand 5α-androstane-3,17-dione. Spirooxazinane steroids Spiromorpholinones are typically synthesized from 1,2-aminoalcohols, often derived from epoxides. In 2008, Poirier et al. reported several (17S)-spiro-(estradiol-17,2'-[1,4

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

• synthesized 44 and 47 with cultured M. alba cells. The formation of both diene 48 and DA adduct 3 were observed, indicating that M. alba cells harbor the key enzymes MaMO and MaDA. Based on these results, synthetic analogs of intermediate 44 were designed and exposed to the M. alba cells to explore the

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• fabrication of visible-light-controlled macroscopic scaffolds, offering the next generation of biomedical materials with visible-light-controlled microenvironments and future soft-robotic systems. Keywords: donor–acceptor Stenhouse adduct; photoresponsive molecular amphiphile; supramolecular transformation

• rearrangement between a barbiturate–furan adduct 4 and compound 3n under ambient conditions in dichloromethane and hexafluoro-2-propanol (HFIP). The synthetic procedures and characterization of all newly synthesized compounds, including DA11, DA7, and DA6, are summarized in Supporting Information File 1

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• first equivalent of aluminum chloride to give the corresponding adduct PIFA–AlCl3. Next, a chlorine atom is transferred to the iodine(III) center to yield I-1–Cl via TS1–Cl with the release of the complex TFAO–AlCl2. Then, the second equivalent of aluminum chloride coordinates the TFAO ligand, giving

• rise to the chlorinating species I-2–Cl in equilibrium with I-3–Cl. At this point, 2-naphthol reacts, leading to the formation of the ion pair I-4–Cl via chlorine atom transfer, which then yields the adduct I-5–Cl trough transition state TS2–Cl. Then, the release of the second equivalent of the TFAO

• –AlCl2 complex yields the final product 1-chloro-2-naphthol (P–Cl). The calculated mechanism for the chlorination reaction starts with coordination of a PIFA oxygen atom to aluminum chloride. This generates a highly exergonic PIFA–AlCl3 adduct. In Figure 1, the Gibbs free energy of this adduct is set as

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• -generated Cu(II)F or NFSI affords the benzyl fluoride. Substrates bearing secondary and tertiary benzylic sites were successful in the reaction. However, primary benzylic substrates were not tolerated, instead affording the N(SO2Ph)2 adduct (e.g., product 13) in moderate yields. The authors noted that

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• -position of the benzene ring, was found to be more reactive as the reaction was completed within 4 h and the desired Michael adduct 3fa was isolated in 89% yield and 92% ee. Notably, the α,β-unsaturated ketone with a substituent in the meta-position of the benzene ring was also tolerated and the desired

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• molecular sieves as water scavengers, but it showed no positive influence on the reaction efficiency (Table 1, entry 20). It should be noted that no competing aza-Michael adduct was monitored in all of the evaluated reaction conditions. According to the above screening results, the generality of the

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• intramolecular Cannizzaro reaction while accomplishing the synthesis of the bicyclic core structure of proposed ottelione A (47) [85]. Commencing from the Diels–Alder adduct 48, an enzymatic desymmetrization of the reduced diol 49 formed the enantiopure 50 (ee >99%). A cascade of reaction sequences delivered the

• nickel(II) complex 96 to the same basic conditions resulted in the formation of the Cannizzaro adduct hemiacetal Ni(II) complex 97 in 56–65% yield predominantly with the byproduct 98 in less than 5% yield (Scheme 26) [93]. Schmalz and coworkers transformed 2-formylarylketones 99 into 3-substituted

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

• conventional metal hydrides, such as tin or silicon hydrides. The reaction mechanism is interesting since first, a Lewis acid–base adduct is generated by interaction of Et3N with a boron atom of bis(catecholato)diboron (B2cat2, 19). As a result, one of the catecholate ligands experiences an increase in

• this protocol. Under basic conditions, the mechanism involves the condensation of a benzoxazolium salt 80, creating NHC–alcohol adduct 81. The [Ir(III)] photocatalyst is excited when exposed to blue light, leading to the formation of a long-lived triplet-excited-state *[Ir(III)] complex. This excited

• -state *[Ir(III)] complex can effectively oxidize the nitrogen atom of activated NHC–alcohol adduct 66 via SET. The resulting nitrogen radical cation intermediate 67 weakens the adjacent C–H bond, making it more acidic and susceptible to deprotonation by a suitable base, ultimately yielding an α-amino

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

• corresponding Ugi adduct 5aa in 42% yield (Scheme 2 and Figure 2). Interestingly, N-benzyl-2-(N-(1-benzyl-3,3-dimethoxy-2-oxoindolin-5-yl)acetamido)-3-hydroxy-2-methylpropanamide (5aa) was obtained rather than the predictable compound with a 3-chloro-2-methylpropanamide group. We believe that a nucleophilic

• –alkyne cycloaddition (CuAAC) reaction, or commonly entitled “click” reaction, is a widely and straightforward tool to access the 1,2,3-triazole ring [26][27]. Due to the presence of an alkyne group on the Ugi-adduct 5bb (Scheme 2) we decided to use the CuAAC reaction to introduce a 1,2,3-triazole unit

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• formation of a hemiacetal intermediate in gilvocarcin biosynthesis [9][38][39] and the AlpH-catalyzed ʟ-glutamylhydrazine adduct formation [14]. Notably, this C12 hydroxy group is absent in the quinone intermediate 3 of the cofactor-dependent pathway. Collectively, these observations suggest that the