Rongalite addition to dienones: diastereoselectivity in cyclic sulfone synthesis; stereochemical rationalization and prospects as a general conjugate nucleophile

• Melina Goga,
• Hao Zong,
• James Franco,
• Jazmine Prana,
• Rudolph Michel,
• Antonia Muro,
• Elana Rubin,
• Janet Brenya,
• Henk Eshuis and
• Magnus W. P. Bebbington

Beilstein J. Org. Chem. 2026, 22, 742–752, doi:10.3762/bjoc.22.56

• substrate may have circumvented this problem, but the necessary double aldol reactions to prepare such substrates, using cyclononanone or cyclodecanone are not known. The difficulties in forming medium-ring ketone enolates have been well described [41]. Rongalite reactivity vs other sulfinates We finally

Synthesis of heterocycles based on azomethine ylides from α-amino acids (or amines) and carbonyl compounds

• Ekaterina V. Berezhnaya,
• Alexander I. Ponyaev,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2026, 22, 705–741, doi:10.3762/bjoc.22.55

• -serine, ʟ-methionine, β-naphthylalanine, phenylglycine, 4-iodophenylalanine, on the achiral Cu(I)/L17 complex leads to the formation of enolates with copper-centered chirality in the form of complex D. Next, complex D interacts with dipolarophiles 53, including fumaronitrile, N-substituted maleimides, β

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• dichloro-magnesium enolates to protected ᴅ-glyceraldehyde [11]. In 1988, Hertel et al. from the Lilly laboratories published the first synthesis of the clinically important anticancer agent gemcitabine, using an intermediate γ-butyrolactone constructed using protected ᴅ-glyceraldehyde and ethyl

• been reported in a 12-step procedure starting with glucose in an overall yield of 2% [24]. Enol esters [25], enolates [26], enamines [27][28], and silyl enol ethers [29], some of which can be derived from LGO, have been used in electrophilic fluorination and trifluoromethylation strategies. It was

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• employing chiral proton sources, such as ᴅ- and ʟ-menthol, (+)- and (–)-camphorsulfonic acid, or pseudoephedrinamide (R,R)-91, proved unsuccessful, as they did not significantly alter the stereochemical preference. Additionally, reversing the quenching order by adding the enolates to acids also failed to

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• yne-allylic cation intermediate, followed by an intramolecular cyclization. The disparity in reactivity could stem from the chelation between acyclic 1,3-dicarbonyl enolates and the copper catalyst, enhancing γ-position attack in an intramolecular manner. Conversely, Meldrum's acid's rigid cyclic

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• originating from unique fluorine atoms or fluorinated groups [1][2][3][4][5][6][7]. During our study in this area, ethyl 4,4,4-trifluorobut-2-enoate (1a) has been frequently employed as a potent and convenient Michael acceptor towards a variety of enolates [8][9][10][11][12][13][14][15] as well as

• , 1519, 1458, 1238, 1204, 1156, 1138, 1097, 1030, 822, 749 cm−1; HRMS–FAB (m/z): [M]+ calcd for C18H18F3NO4, 369.1182; found, 369.1209. General procedure for the ring opening of epoxides by enolates (GP-3). 4-Benzyl 5-ethyl anti,syn-tetrahydro-2-oxo-3-(trifluoromethyl)-furan-4,5-dicarboxylate (anti,syn

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

• with diketenes (Scheme 1b, path 3) [35] as well as isocyanates with various nucleophilic reagents (Scheme 1b, path 4), such as silyl enol ethers [36], enamines [37], α-acylphosphonium ylides [38] and lithium enolates [39]. Recently, the hydrolysis of α-oxo ketene N,S-acetals was developed to prepare

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

• -dicarbonyl compounds and their one-pot transformation pave the way for MCR syntheses of pyrazoles. 1,3-Dicarbonyl compounds can, for example, be generated in situ from enolates and carboxylic acid chlorides. They can be converted to the corresponding pyrazoles 1 in a consecutive multicomponent reaction with

• 11 are formed via Hantzsch's thiazole synthesis. After acidic deprotection to thiazolylhydrazines 12, these react with enolates of 2,4-diketoesters, which are intermediaries prepared in a separate reaction vessel, yielding the corresponding (thiazol-2-yl)pyrazoles 8. However, hydrazines are not

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

• the uncoordinated anion when calculated as isolated structures. When the calculation is performed as a reaction of E and Z-enolates with Cs+ ion, two coordinated complexes 6(N-H)NNCs-E and-6(N-H)NOCs-Z are exergonically formed by 9.7 and 10.9 kcal/mol, respectively. We then searched for transition

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• anionic 1a–i-enolate species in parallel with N-fluoroammonium ion 6. Fluoride ions formed through the reactions between fluorine and quinuclidine or fluorine and enolate species, may deprotonate 1a–i-enol, to form enolates of 1a–i that are reactive towards both fluorine and N-fluoroammonium ion 6. The

• pKa(MeCN) of 1a-keto is ≈26.3, and we expect a pKa(MeCN) of 2a-keto to be similar in value [51][52], we suggest fluoride ion may be sufficiently basic to cause significant acceleration of the deprotonation of 2a–i-keto and allow formation of 2a–i-enolates, which then react rapidly with fluorine gas

• as an effective base for the formation of enolates of 1a and 2a, and this is reflected in the modest levels of formation of 3a (Scheme 4). Chloride ion, on the other hand, is less basic (pKa(MeCN) of HCl is 10.30 [60]), however, its greater solubility seemingly allows some level of deprotonation of

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

• stereocenters [7]. In the Review paper by Kisszékelyi and Šebesta, the diverse variety of chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents and the possibilities to engage metal enolates in tandem reactions with new electrophiles are presented [8]. A Perspective from X

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• atom to zinc enables this SH2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical. The zinc enolate thus formed readily undergoes β-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N–H bonds undergo

• carbonyl compounds to provide the corresponding zinc enolates (Scheme 1) [1][2]. While simple, this reaction offers attractive features: 1) it proceeds under mild conditions in the absence of any transition-metal catalyst; 2) the 1,4-addition step can be combined with condensation reactions of the zinc

• coordinated to the zinc atom: this offers a gain in enthalpy associated to the formation of zinc enolates stabilized by chelation and increases the spin density delocalized at the oxygen atom involved in the chelate. Note that the reported 1,4-additions of dialkylzinc reagents to alkylidenemalonates could

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

• enolates in high enantiomeric purities. These enolates are reacted with highly electrophilic onium compounds to afford densely substituted acylimidazoles. DFT calculations helped to understand the reactivity of the zinc enolates derived from acylimidazoles and allowed their comparison with metal enolates

• products [20]. A salient feature of conjugate additions of organometallic reagents is that they generate reactive metal enolates as primary products. These enolates can be used in a variety of subsequent transformations [21]. Chiral enolates generated by conjugate additions react with carbonyl compounds

• , imines, other Michael acceptors, or alkyl halides. Our group is developing trapping of metal enolates with stabilized carbocations and could show that magnesium enolates generated from enones [22], unsaturated amides [23], or heterocycles reacted with tropylium, dithiolylium or flavylium cations [24

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• Peter Kisszekelyi Radovan Sebesta Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University Bratislava, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia 10.3762/bjoc.19.44 Abstract Metal enolates are useful intermediates and building blocks indispensable in many

• organic synthetic transformations. Chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents are structurally complex intermediates that can be employed in many transformations. In this review, we describe this burgeoning field that is reaching maturity after more than 25

• years of development. The effort of our group to broaden possibilities to engage metal enolates in reactions with new electrophiles is described. The material is divided according to the organometallic reagent employed in the conjugate addition step, and thus to the particular metal enolate formed

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• bridged α,β-unsaturated ketones; however, these reactions do not involve initiation by an oxa-Michael addition [23][24]. The reaction between 1 and aromatic ketones under basic conditions is analogous to the well-known aldol/Michael cascade reaction observed between aldehydes and enolates giving di- and

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• , epimerization is prevented through deprotonation of amide NH bonds, as argued by Seebach for Li enolates [53][54]. Nevertheless, isoleucine was prone to epimerize under the reaction conditions due to its vicinity to proline and therewith lack of the “protecting” NH group. Since no full conversion was observed

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• charged intermediates, could be an excellent methodology for the enantioselective SN2 alkylation of enolates derived from the 2-oxindole core [13][14][15][16][17][18][19][20][21][22][23]. In recent years, several examples regarding the alkylation of 3-subsituted-2-oxindoles, via asymmetric phase-transfer

• could be possible to develop an effective catalytic asymmetric protocol. To the best of our knowledge such base-free catalytic systems have never been applied to processes such as the alkylation of enolates generated in situ. These reactions would produce stoichiometric amounts of acid, which can

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)

• Tania Xavier,
• Sylvie Condon,
• Christophe Pichon,
• Erwan Le Gall and
• Marc Presset

Beilstein J. Org. Chem. 2021, 17, 2085–2094, doi:10.3762/bjoc.17.135

• known as alkyl hydrogen malonates or hemimalonates, constitute an attractive class of pronucleophiles in the design of eco-compatible syntheses [1]. Indeed, they can serve as efficient precursors of ester enolates through decarboxylation [2][3], generally using a substoichiometric amount of a weak base

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• -substituted glutamate derivatives is via the Michael addition of α-amino ester enolates to acrylate acceptors. These products can also be easily converted to pyroglutamates by lactamization [28][29][30]. Although the use of substituted amino ester derivatives for the enantioselective α-alkylation has been

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• -fluorosultams were stable below 100 °C. The enantioselectivities of products were examined after the fluorination of different metal enolates. In the best case a 63% yield and 70% enantiomeric excess (ee) was obtained. Even though other products gave less satisfactory outcomes, the potential of the N-F

• carbanions (Scheme 29). For example, reactions with enolates gave α-fluorinated products in 65–100% yields. Azaenolates could be fluorinated in moderate yields. A fluorination reaction with phenylmagnesium bromide provided fluorobenzene in 80% yield, an outcome which was better than that of N

• -dichlorocamphorsultam) 17-2 [75] (Scheme 37). The maximum enantioselectivity of enolates of β-ketoesters with (−)-9-1 or (+)-9-2, first prepared by Lang in 1988 (see section 1-9), was 70% ee. The asymmetric fluorination with (+)- or (−)-17-2 afforded up to 75% ee as indicated in Scheme 38. The dichloro reagent 17-2

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• -containing 1,2,3-triazole derivatives 30 from the reaction of glycosyl azides 28 with enolates of active ketones and esters 29 in the presence of DBU in DMF at 70 °C (Scheme 12) [43]. Diverse monosaccharide and disaccharide azides were successfully reacted with a variety of enolates of active ketones and

• through the regioselective addition and cyclization reaction of EDAMs 24 with p-methylbenzenesulfonyl azide. Synthesis of 1,4,5-trisubstituted glycosyl-containing 1,2,3-triazole derivatives 30 from the reaction of glycosyl azides 28 with enolates of active

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• of a Lewis acid (LA) to activate 1,3-dicarbonyls through the formation of metallic enolates was recently explored by Schindler’s group for the intramolecular tert-alkylation of prenylated β-keto esters 103 (Scheme 39A

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• -bromoenolates to enantiopure p-toluenesulfinamide 5. cis-aziridine 7a was formed as the major diastereoisomer in 89% yield and the trans-isomer in 8% yield in a one-step procedure using lithium enolates of methyl bromoacetate 6a and sulfinyl imine 5. Lithium enolates of methyl α-bromopropionate gave trans

• the Grignard reagent in this synthesis, with a 18% overall yield after seven steps from aldimine ent-126 (Scheme 35) [125]. The reaction of chiral α-siloxyl imine (SS)-126 with enolates derived from methyl ketones 131 was also investigated. The enolate was formed with LDA at −78 °C and reacted at the

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• hexafluorophosphate (4) and TEMPO (3) were subsequently added to trigger the single electron oxidation of the formed amide enolates and radical oxygenation affording α-(aminoxy)amides 9a–n in good 51–77% isolated yields. Cyclic units in the allylic N-substituent (Table 2, entries 14 and 15) and the epoxide (Table 2

• ROESY investigations (see Supporting Information File 1). This corresponds to the previously reported data for N-benzylacetamides [82]. It can be assumed that the amide enolates after the Brook rearrangement and the α-amide radicals (4S,S)-19i–k and (4R,S)-19i, respectively, resulting after SET