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

• challenging iminoiodinanes). In situ preparation of the iminoiodinane intermediates is possible, and for those reagents that undergo facile decomposition, aziridination is more efficient using these conditions (yields for in situ-generated iminoiodinanes are in parentheses in Scheme 3, with N-o-methyl (6g

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

• structural characters and multiple good reactivities [1][2][3][4]. Both β-keto thioesters [5][6][7][8][9][10][11][12] and β-keto amides [13][14][15][16][17][18][19][20][21][22] have served as useful synthetic intermediates for the synthesis of a range of potent natural products. Therefore, much effort has

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

• intermediates [34] (e.g., G) or side products [35] (e.g., H) during their total synthesis, are neither systematically covered in this review. A number of wrongly assigned structures have been proposed over the decades (Figure 3). These are mentioned here in summary, where further details will be given in the

• fecal microbiota [107]. Alternariol methyl ethers: Methyl ethers of alternariol have been obtained during chemical structure elucidation and as intermediates in total syntheses of natural products, but some of these have been furthermore isolated as natural products (Figure 5). First to mention is 9-O

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

• (R = EWG-C6H4, E = PhS and PhTe) in moderate to high yields [30]. Very few examples of intermolecular cascade reactions with imidoyl radicals as key intermediates have been reported. The intermolecular cascade reaction of diselenide, electron-deficient acetylene, and isocyanide under photoirradiation

• isocyanides forms boron-substituted imidoyl radical intermediates and rapid β-scission then causes elimination of the substituents on the nitrogen (Scheme 12) [53]. Radical cyclization via formation of imidoyl radical species In the former chapter, we discussed 1,1-addition reactions of typical element

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

• of the carbonyl groups and their derivatives. 1,3-Dicarbonyl compounds as key intermediates The most common and classic synthesis of ring-forming pyrazoles is the cyclocondensation of 1,3-dicarbonyl compounds with hydrazines (Knorr synthesis) [42][43]. Therefore, the in situ generation of 1,3

• , 3,4,5-substituted pyrazoles 5 are formed (Scheme 2) [45]. The Lewis acid catalyst accelerates the reaction via participation in the formation of β-diketonate complexes. Other carbonyl compounds suitable for pyrazole synthesis are 2,4-diketoesters 13. These intermediates can be prepared from diethyl

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

• access to diazo compounds as either synthetic intermediates or products. A special attention is paid to the reaction mechanism with the aim to encourage further development in this field. Keywords: C–H functionalization; diazo compound; electrosynthesis; hydrazone; nitrogen-containing heterocycle

• have been harnessed as valuable intermediates in Wolff–Kishner reduction reactions [12][13][14] or for the synthesis of various olefins via diazo or vinyllithium intermediates in the Bamford–Stevens reaction [15] and Shapiro reaction [16], respectively [17]. SAMP/RAMP ((S)/(R)-1-amino-2

• -methoxymethylpyrrolidine)hydrazones could be also key intermediates for the asymmetric synthesis of α-substituted aldehydes and ketones [18][19]. Interestingly, depending on the substitution pattern, the C=N bond can feature different electronic properties [20]. For instance, various hydrazones have been employed for the

Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• Abstract A flow photochemical reaction system for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence was developed, which utilizes in situ-generated 2-benzopyrylium intermediates as the photoredox catalyst and electrophilic substrates. The key 2-benzopyrylium intermediates were

• generated in the flow reaction system through the intramolecular cyclization of ortho-carbonyl alkynylbenzene derivatives by the π-Lewis acidic metal catalyst AgNTf2 and the subsequent proto-demetalation with trifluoroacetic acid. The 2-benzopyrylium intermediates underwent further photoreactions with

• catalytic cycles). In catalytic cycle I, the key cationic components, 2-benzopyrylium intermediates A, are generated in situ by the activation of the alkyne moiety of ortho-carbonyl alkynylbenzene derivatives 1 in the presence of the π-Lewis acidic metal catalyst [M]X [AgNTf2 or Cu(NTf2)2] and subsequent

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• state (TS) structures that would produce both the N1- and N2-products from CH3OTs as a model system. When the Boltzmann average of the cesium-coordinated intermediates is calculated, a 3:1 ratio of 6(N-H)NOCs-Z:6(N-H)NNCs-E is found. This average is 10.6 kcal/mol more stable than 6(N-H), and was

• favorable under conditions A. Postulating that O or N-dative interactions with phosphorus were responsible for the high N2-selectivity in an analogous fashion to conditions A, we searched for intermediates and TSs that included this possibility. No O–P or N2–P-coordinated intermediates were found. The

• indazole and the deprotonated indazole was only −0.2 kcal/mol (Figure 11). Again, no preorganized intermediates were found. The NCIs were consistent with the parent system. The hydrogen bond between the H on the electrophilic methyl group and an ester oxygen was found in the transition state leading to the

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• that α-heteroaryl acetates accessed through Negishi coupling can be used as key intermediates towards NCAs (Scheme 1c). Indeed, oximation of these motifs followed by reduction gave access to the desired NCAs. Results and Discussion Negishi cross-coupling step The Negishi reaction provides convenient

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• radical clock experiment was carried out with 1d under the optimal reaction conditions, resulting in the formation of 2d in 54% yield, and no cyclopropyl ring opening products were observed. This result suggested that no radical intermediates were generated during the reaction (Scheme 5). According to the

• the substrate, and thus preventing the possible interaction between the amide moiety and PISA, as opposed to CH3CN. The olefin moiety of the complex then interacts with the exposed central iodine(III) atom in PISA [25], forming the intermediate D. Similar cyclic iodonium intermediates were also

• HFIP (3.0 mL) at room temperature. Isolated yield is stated. aThe yield of 2k was 56%. bThe yield of 2m was 24%. cThe yield of 2n was 11%. Control experiment to test for radical intermediates. Proposed mechanism for the reaction between 1a and PISA in anhydrous acetonitrile. Two other resonance

Electrochemical radical cation aza-Wacker cyclizations

• Sota Adachi and
• Yohei Okada

Beilstein J. Org. Chem. 2024, 20, 1900–1905, doi:10.3762/bjoc.20.165

• cations that offer unique reactivities as intermediates in various bond-formation processes. Such intermediates can potentially take part in both radical and ionic bond formation; however, the mechanisms involved are complicated and not fully understood. Herein, we report electrochemical radical cation

• organic chemistry [11][12][13][14][15]. Single-electron oxidation of bench-stable substrates can generate radical cations that offer unique reactivities as intermediates for various bond-formation processes (also true for reduction). Because the reactivities of radicals and ions are fundamentally

• different, their creative use may pave the way for complementary bond formation. This merging is unique and such intermediates could potentially take part in both radical and ionic bond formation. However, the mechanisms involved can be complicated and are not fully understood. Alkenes and styrenes are

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

• , was not observed. In 2016, Sashidhara et al. reported the catalytic effect of Ag(OTf) on GBB reactions, postulating its role in activating the attack of the isocyanides onto the imine intermediates [7]; some years later Liu et al. reported a similar role of AgOAc [8]. Although the reaction was tested

• compatibility of the GBB reaction with typical KTGS conditions, such as aqueous solvent at near-physiological pH and high dilution, and the achievement of selective ligand amplification. First, molecular modeling studies were carried out to verify that building blocks and intermediates could bind the target

• yield of 83–95%. The second strategy, based on the deacetylation of 29 followed by the GBB-3CR, led to a lower overall yield of 21–23%. The reaction with different 2-aminopyridines and alkyl/aryl isocyanides afforded the intermediates 30 in 86 to 96% yield, and the subsequent deacetylation with

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

• that bear two functional groups. In order to avoid competitive reactions, these groups need to be compatible with the components of the Ugi reaction or the intermediates generated during the reaction. Thus, an amine can rarely be directly incorporated as an additional functional group, because of

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

• % by condensing unsaturated ketones 84 with aniline under refluxing ethanol. These intermediates were then subjected to a reaction with excess mercaptoacetic acid (also known as thioglycolic acid) in refluxing benzene, resulting in the formation of spiro 1,3-thiazolidin-4-one derivatives with good

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

• using an enzyme or at what stage in a synthesis the enzyme is employed: 1) regio- and stereoselective late-stage functionalization of core scaffolds, 2) in situ generation of highly reactive intermediates, and 3) the one-step construction of macrocyclic or fused multicyclic scaffolds via regio- and

• pathways are described with a focus on the biosynthetic intermediates and enzymatic transformations that enable cascade reactions and pinpoint modifications. This focus highlights how these biosynthetic pathways are applicable to the development of streamlined chemo-enzymatic synthesis processes. The

• discussion will also encompass the design of biosynthetic intermediates and their analogs to achieve chemo-enzymatic total syntheses. Given our emphasis on natural products, this review does not cover the exquisite synthetic approaches involving biocatalysts for small-molecule pharmaceuticals. To gain a more

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• strategy is founded on the build and release of molecular strain and achieves a formal transposition of a methyl group. During light irradiation, 3-phenylazetidinols are forged as reaction intermediates, which readily undergo ring opening upon the addition of electron-deficient ketones or boronic acids

• stringent demands on the selection and assessment of substrates. In our quest to identify a suitable system, we were attracted by the use of azetidines as potential reaction intermediates (Scheme 1b) [8][9][10]. Azetidines were chosen because of existing literature precedent for their photochemical assembly

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• remethylated to ʟ-methionine by the enzyme methionine synthase, which utilises 5-methyltetrahydrolate (5-MTHF) as a methyl donor. 5-MTHF is a constituent of the folate cycle, which encompasses the intermediates tetrahydrofolate (THF) and 5,10-methylene-THF (5,10-CH2-THF). 5,10-CH2-THF is formed from THF and ʟ

• aspartimide intermediates (Figure 6). The activity of most PAMTs depends on a cyclised precursor peptide. Modification of the aspartate/isoaspartate residue was found only in a hairpin-like or the macrocyclic region [71][78]. The underlying purpose of this structural requirement of PAMTs has not yet been

• -MT [114]. PbtM1 methylates Asn4 in the GE2270 precursor peptide. Substrate specificity appears to be pronounced, as amino acid substitutions in the core were not tolerated by the biosynthetic machinery. PtbM1 acts independently of other modifications since linear intermediates after enzyme deletion

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• industry to implement such C–H transformations to diversify different types of molecules ranging from small drug-like molecules to intermediates and lead compounds. Especially late-stage functionalization is a promising emerging field that allows chemists to efficiently explore the chemical space in

• pharmaceutical intermediates that undergo selective borylation to compare our QM workflow and ML model with experimentally determined reaction sites. The quantum chemistry-based workflow Following work by Ree et al. [12][13][14][15], we present a fully automated QM-based workflow for computing C–H pKa values. A

• ] and experimentally validated their approach using six pharmaceutical intermediates from medicinal chemistry programs. In the article, they state that ”Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the aryl C–H bonds that are most acidic and least sterically hindered…”[45

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

• , the 6-31G(d) basis set was used for the other atoms (i.e., H, C, O, F, Al, etc.). Geometry optimizations were carried out without any symmetry constraints, and the stationary points were characterized by analytical frequency calculations, i.e., energy minima (reactants, intermediates, and products

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

• ; quinoline; Introduction Nitrogen-containing molecules are important bioactive compounds and intermediates in chemical synthesis. Therefore, the chemical transformations of nitrogen-containing compounds have been widely studied in the field of organic synthesis [1][2][3][4]. For instance, the reduction of

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

• -fluorobenzoates as both photocatalysts or photo-auxiliaries and was demonstrated on a number of benzylic examples. Photochemical Photochemical methods have proven to be powerful tools in the generation of reactive intermediates, including benzylic radicals [64][65][66][67]. Oxidative photochemical

• yields, with the authors proposing that HFIP aided in stabilising the electrochemically generated benzylic radical cation intermediates. Secondary and tertiary benzylic substrates bearing halogen, ester, protected amine and alkyl functional groups tolerated the reaction conditions well. The authors

• showed they were able to scale-up and selectively fluorinate the ibuprofen methyl ester at the methylene group to produce over 2 g of product 12. The utility of the benzyl fluoride products as strategic intermediates for benzylation of electron-rich arenes was demonstrated by the authors (Figure 41B

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• . Based on these mechanistic details obtained so far, we were also wondering if we could get any hints concerning possible reaction intermediates. Ishihara’s group recently showed that their α-azidation protocol proceeds via in situ α-iodination first, followed by nucleophilic displacement by the azide

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• intermediates in organic synthesis for the construction of all-carbon-substituted quaternary centers (Figure 1A). However, conventional methods for the synthesis of tertiary alkylnitriles such as direct functionalization of alkylnitriles [10] and hydrocyanation of alkenes [11][12][13][14] are typically hindered

• have provided innovative strategies, substrates in all of these reaction systems are generally limited to benzylic, α-amino-, and α-oxy aliphatic acids, presumably due to the necessity of stabilized radical intermediates for the following radical cyanation step. We and others have recently demonstrated

• investigated (Figure 2). Arylacetic acids with relatively stable benzylic radicals as the corresponding intermediates have been proved to be suitable substrates to the reaction, providing the desired decarboxylative cyanation products with generally good yields (2–18). To show the synthetic potential of this

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• embedded in the assembly line or not. All cis-AT PKS modules contain a ketosynthase (KS), an acyltransferase (AT), and an acyl carrier protein (ACP) to produce β-keto-intermediates, and some modules contain additional β-processing domains such as ketoreductase (KR), dehydratase (DH), and enoylreductase (ER

• epimerization of α-substituted intermediates. The lack of the conserved GM (11) motif preceding the αFG helix, which is highly conserved in other types of reductase-competent KRs, was also observed in A2-type KRs. The absence of this region in the electron density map of the A2-type AmpKR11 [30] may indicate a

• ) motif. These observations suggest several possibilities: (1) the stereoselectivity prediction for KRs in γ- and δ-modules is inaccurate, (2) a cis (Z) double bond can also be produced from ᴅ-β-hydroxyacyl intermediates due to a different substrate binding mode in DH [7], or (3) a cis (Z) double bond is

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

• -benzyl-N-substituted anilines. In this work, (E)-2-arylidene-3-cyclohexenones firstly react with primary amines to form cyclohexenylimine intermediates I. Afterward, isoaromatization resulting from imine–enamine tautomerization and exocyclic double bond shift occurs to give rise to stable aniline