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

• confirmed that a copper–ligand monomer complex exists in the mechanism through nonlinear relationship experiments and kinetic studies (Scheme 17). He et al. [68] developed the regio- and enantioselective monofluoroalkylation of yne-allylic esters using fluorinated malonates as the starting materials, giving

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

• executed at −78 °C under the action of LDA [29]. Moreover, by using the epoxyester 2b as the representative substrate, clarification of its reactivity was carried out by mixing with 1) heteronucleophiles like amines, thiols, and magnesium halides, 2) softer carbon nucleophiles such as malonates, and 3

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

• attention. The controlled formation of C–C and C–X bonds in a stereoselective fashion has found extensive application in asymmetric synthesis. Notably, the addition of malonates has attracted significant interest, albeit primarily limited to methyl or ethyl diesters [18][19][20]. The combination of iminium

• time of two days under a pressure of 0.8 GPa [23]. Less reactive benzyl malonates, which allow for the cleavage of a free carboxylic group without the need for harsh base- or acid-mediated conditions [24], undergo additions catalyzed by primary amines [19]. However, these transformations are hampered

• low conversions and stereoselectivities when applied to benzylidene acetones or cyclic enones (vide infra). In our latest research in establishing a mild organocatalytic protocol for incorporating benzyl malonates and bisthiomalonates into cyclic enones and benzylidene acetones, we have developed a

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

• methodology (Table 2). At first, various arylidenemalonates 2 were tested with a phenyl analog of curcumin 1. The reaction of 1a with arylidene malonates 2a–c, bearing weakly electron-withdrawing para-substituents, produced the corresponding double Michael adducts 3a–c, respectively, in good to high yields

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• oxidative alkylation of cyclic benzyl ethers with malonates or ketones. Oxygen is used as a terminal oxidant at atmospheric pressure. The key intermediate of this oxidative coupling reaction is benzyl alcohol intermediate C (Scheme 4) [52]. The generation of N–O radicals from NHPI in the presence of oxygen

First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• compounds to give diarylated (oxoalkyl)malonates [6]. In the reaction using tin(II) chloride as the Lewis acid, the ring opening and nucleophilic attack of the nitro group occur, to produce functionalized isoxazolines (reaction d) [7]. In contrast, denitration under basic conditions generates highly

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• unsubstituted as well as chloro-substituted derivatives of 1a. Storz et al. [44] have reported on an analogous method to prepare dibenzo[b,f]oxepines 1b through the rearrangement of 9-(α-hydroxyalkyl)xanthenes. 2.2 Ring expansion of 2-(9-xanthenyl)malonates Oxidative ring expansion of 2-(9-xanthenyl)malonates

• )malonates 24. Ring expansion via C–H functionalisation. The synthesis of fluorinated 5H-dibenzo[b,f]azepine 38 from isatin (32). The synthesis of substituted dibenzo[b,f]azepines 43 from indoles 39. Retrosynthetic pathways to dibenzo[b,f]azepines via Buchwald–Hartwig amination. Synthesis of dibenzo[b,f

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• functionalization is still challenging for chemists to combine a C(sp3) carbon of incoming functionalities and C(sp2) carbon of the IP core. The direct C-3 alkylation of imidazopyridines using active malonates and related moieties has been achieved by different routes [17][18][19][20]. However, these reactions rely

• each on the pyridine ring. Moreover, IPs with a non-aromatic C-2 substituent like an ester group were also included (4r). We also explored bromo analogues of other active methylenes such as ethyl cyanoacetate, ethyl acetoacetate, dimethyl, and diisopropyl malonates, as extension of diethyl malonate (4s

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• malonates [25]. Herein, we report the results of an asymmetric organocatalytic Michael addition of CPD to alkylidene oxindoles. Results and Discussion Chiral multifunctional thioureas [26][27] and squaramides [28] are extensively used as catalysts in asymmetric Michael additions. We believed that a

Solvent-free synthesis of enantioenriched β-silyl nitroalkanes under organocatalytic conditions

• Akhil K. Dubey and
• Raghunath Chowdhury

Beilstein J. Org. Chem. 2021, 17, 2642–2649, doi:10.3762/bjoc.17.177

• -silylmethylene malonates (Scheme 1b) [29]. As the catalytic enantioselective route is limited to accessible β-nitrosilanes, there is an urgent need to develop efficient catalytic protocols to deliver enantioenriched β-nitrosilanes from easily available starting materials. Metal-catalyzed reaction of various

Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

• Siyu Wang,
• Lianyou Zheng,
• Shutao Wang,
• Shulin Ning,
• Zhuoqi Zhang and
• Jinbao Xiang

Beilstein J. Org. Chem. 2021, 17, 2505–2510, doi:10.3762/bjoc.17.167

• . However, these reactions were mainly suitable to strong nucleophiles such as malonates, amines, or alcohols etc. [20][21][22][23]. The allylic substitution reactions using some weak nucleophiles, such as alkyl aza-arenes, were very limited [24][25][26][27][28][29]. In 2014, Rios and coworkers developed a

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

• affords the advantage of being based on commercially available malonates. We thus envisioned to achieve the alkylation step by deprotonation of a malonate with NaH followed by treatment with a halogenated compound. As our first attempts revealed a strong influence of the stoichiometry and the nature of

• could be isolated in 70% and 47% yield, respectively (Scheme 2). Ester modification Meldrum's acid route We next turned our attention to the diversification of the ester group of SMAHOs. Our first approach was the use of substituted malonates, protected as Meldrum's acid derivatives, as the parent

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

• -(trimethylsiloxy)pyridine was allowed to react with 5% F2 diluted with N2 in a freon solvent at −78 °C, 1-fluoro-2-pyridone was obtained in 63% yield (Scheme 5). The fluorination efficiency of 3-1 was higher than perfluoro-N-fluoropiperidine (1-1) and the yields of reaction with sodium diethyl malonates improved

• malonates and Grignard reagents were largely improved to up to 81% and 50%, respectively. The carbanions of aromatics, ketones, nitroalkanes, amides, etc. could also be reasonably well fluorinated and this study showed great progress. However, although these fluorinating agents were stable and easy-to

• , SelectfluorTM, from a cost-effectiveness viewpoint. The fluorinating power of reagents 16-3 strengthened as the electronegativity of the R group increased in the order of CH3 < CH2Cl < CH2CF3. The reagents 16-3 were able to fluorinate enol and conjugated enol acetates of steroids, sodium malonates, enamines

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

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

• under solvent-free conditions was carried out, using sodium carbonate as base promoter. The resulting dimethyl 2-(1-aminoalkyl)malonates 50 were obtained in moderate to good yields as single diastereoisomers in all cases except for aromatic aldimines. Compounds 50 could be easily transformed

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• CBr4 or I2, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or NaH as the base, and a malonate-derived substrate. The adduct is synthesized in a slightly higher yield by direct treatment of fullerene with malonates. As noted above, a decrease in the strain of the fullerene core is the driving force of its

• N2 extrusion. Therein, the formed [5,6]-opened adducts are transformed into [6,6]-closed isomers, which are more thermodynamically stable. While the range of reagents used in nucleophilic cyclopropanation with stabilized carbanions is mainly limited to malonates, the range of cyclopropanating agents

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• ). Alternative electrophilic components for the Eschenmoser coupling reaction The Eschenmoser coupling reaction [36][37] usually starts from α-substituted ketones, esters, malonates, or nitriles. The group in the α-position must be a good leaving group enabling a facile nucleophilic substitution giving the α

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• compounds in the PK reaction started with fluorinated enynes derived from malonates and those containing heteroatoms as linkers. The synthesis of the starting enynes 37 was accomplished following various approaches (Scheme 19). The first of these (via a) was based on a report by Hammond and co-workers, in

Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

• Carlos H. Escalante,
• Eder I. Martínez-Mora,
• Carlos Espinoza-Hicks,
• Alejandro A. Camacho-Dávila,
• Fernando R. Ramos-Morales,
• Francisco Delgado and
• Joaquín Tamariz

Beilstein J. Org. Chem. 2020, 16, 1320–1334, doi:10.3762/bjoc.16.113

• similar chemoselectivity has been previously observed, being explained as a consequence of the acidity of the C–H bond being cleaved [6][44]. Additional intramolecular cross-coupling reactions were carried out by utilizing dimethyl malonates 8k and 8l, which were prepared through the N-benzylation of 16c

Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

• Kaj M. van Vliet,
• Nicole S. van Leeuwen,
• Albert M. Brouwer and
• Bas de Bruin

Beilstein J. Org. Chem. 2020, 16, 398–408, doi:10.3762/bjoc.16.38

• compound, with applications ranging from thickening agents (carboxymethyl cellulose, E466) [1][2], herbicides (2,4-dichlorophenoxyacetic acid), cosmetics (cocamidopropyl betaine), dyes (indigo vat dye) [3], to pharmaceuticals (ibuprofen, glycine, malonates) [4] (see Figure 1). Many reactions with

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• by cyclocondensation with ketene dithioacetals and substituted acetophenones other cyano-containing derivatives became accessible by desymmetrizing cyclocondensation of 1,2-diaroylacetylenes with ethyl cyanoacetate [27], similar to related studies with dialkyl malonates [28]. Here, we report on

• of dialkyl malonates in a Michael addition–cyclocondensation to form α-pyrones (Scheme 1). With this sequence in hand, we envisioned the variation of CH-acidic esters to generate differently 3-substituted α-pyrones. For introducing a cyano substituent we employed benzoyl chloride (1a

• -pyrones from acid chlorides, terminal alkynes and dialkyl malonates. Consecutive pseudo-four-component alkynylation–Michael addition–cyclocondensation (AMAC) synthesis of 1H-pyridines 5a and an aniline derivative. Consecutive pseudo-four-component alkynylation–Michael addition–cyclocondensation (AMAC

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• reaction with their participation. Asymmetric conjugate addition of activated methylene compounds (such as diketones, keto esters and malonates) to nitroalkenes in the presence of Mg [43], Co [44][45], Mn [45] and Ru [46] complexes was performed. The most remarkable results were obtained with Ni(II

Oxidative radical ring-opening/cyclization of cyclopropane derivatives

• Yu Liu,
• Qiao-Lin Wang,
• Zan Chen,
• Cong-Shan Zhou,
• Bi-Quan Xiong,
• Pan-Liang Zhang,
• Chang-An Yang and
• Quan Zhou

Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

• for the Mn(OAc)3-mediated oxidative radical ring-opening and cyclization of MCPs with malonates is outlined in Scheme 2. Initially, the malonic acid diethyl ester (2) was transformed into radical 4 [44] under the action of Mn(OAc)3. Then, the selective addition of the radical 4 to the C–C double bond

• oxidative radical ring-opening/cyclization of cyclopropane derivatives. Mn(OAc)3-mediated oxidative radical ring-opening and cyclization of MCPs with malonates. Mn(III)-mediated oxidative radical ring-opening and cyclization of MCPs with 1,3-dicarbonyl compounds. Heat-promoted ring-opening/cyclization of

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

• Eloi P. Coutant,
• Vincent Hervin,
• Glwadys Gagnot,
• Candice Ford,
• Racha Baatallah and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2853–2860, doi:10.3762/bjoc.14.264

• was used for the historic preparation of racemic lysine from diethyl malonate and γ-chlorobutyronitrile [4] and appears to be of a very large scope. The key α-hydroxyimino esters 2 precursors to the α-amino esters 1 are usually prepared by oximation of substituted malonates 3, themselves made, for

• –al led to the substituted malonates 3a–al. A simple and general procedure was adopted for the condensation using fairly concentrated ethanolic solutions of diethyl malonate (4) and aldehydes 5a–al along with catalytic amounts of piperidine and acetic acid as well as some 4 Å molecular sieves to trap

• the water formed in situ. The 1H NMR monitoring of crude samples pointed out a complete conversion, most often overnight at 60 °C, and the resulting solutions of alkylidenemalonates 6a–al were then directly reduced to give the malonates 3a–al. For this reduction step, palladium-based catalytic

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• acid as a catalyst had to be heated at 60 °C for a few hours to secure a similar conversion into pivalal 8. From intermediates 7 and 8, and as previously reported in the case of malonates [17][18][19], we then hoped for an improvement of their condensation with ethyl nitroacetate (4). The 1H NMR