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

A novel recyclable organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen

• Gyula Dargó,
• Dóra Erdélyi,
• Balázs Molnár,
• Péter Kisszékelyi,
• Zsófia Garádi and
• József Kupai

Beilstein J. Org. Chem. 2023, 19, 1811–1824, doi:10.3762/bjoc.19.133

• , application, and recycling of a new lipophilic cinchona squaramide organocatalyst. The synthesized lipophilic organocatalyst was applied in Michael additions. The catalyst was utilized to promote the Michael addition of cyclohexyl Meldrum’s acid to 4-chloro-trans-β-nitrostyrene (quantitative yield, up to 96

• reaction could be used in the synthesis of several drugs to form a carbon–carbon bond in a stereoselective manner [6][35]. Our goal was to synthesize the chiral precursor 17 of baclofen (Scheme 3). To achieve this objective, we first planned to use Meldrum’s acid and 4-chloro-trans-β-nitrostyrene (16

• ). Based on the literature [36], Meldrum’s acid has a low solubility in non-polar solvents, resulting in diminished enantioselectivity. Furthermore, in our case, the application of polar solvents would not be favorable due to the low solubility of the lipophilic organocatalyst in these solvents

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• potentials of 0.075 e and 0.048 e. The cyclic dimedone-derived ylide I-12 showed similar potentials of 0.080 e and 0.052 e, as did the Meldrum’s acid-derived ylide I-13 (0.085 e and 0.057 e). Whether the ylide was cyclic or acyclic, the σ-hole opposite the β-dicarbonyl motif was consistently greater in

• and Liang modified the iodonium ylide’s β-dicarbonyl skeleton (Scheme 11), and while derivatives of barbituric acid (54a) and Meldrum’s acid (54b) were moderately effective, replacing the gem-dimethyl with spirocyclic motifs 54c–e provided [18F]fluorobiphenyl 55 in 47–85% yield [134]. Decomposition

• ]. Computational investigations were conducted to better understand these reactions, and it was determined that the changing alkyl motif (e.g., dimethyl, cyclopentyl, adamantyl) had minimal impact on the activation energy of the fluorination reactions. The reaction coordinate was calculated for Meldrum’s acid

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• using aldehydes and Meldrum’s acid under metal-free and mild reaction conditions [20]. The optimization conditions were estimated to be 1.0 mmol of 1-benzyl-4,5-dimethylimidazole N-oxide as substrate, 1.0 mmol of aldehydes and 1.0 mmol of Meldrum’s acid (26) in 6.0 mL of acetonitrile as solvent at

• reflux for 5 h. In this operationally simple procedure, the imidazole N-oxide plays the role of a ‘C’-nucleophile when there is no involvement of acid or base catalyst. 1-Benzyl-4,5-dimethylimidazole N-oxide (28) was chosen as the N-oxide substrate to react with Meldrum’s acid (26) and several aldehydes

• reaction of Meldrum’s acid (26) and aldehyde 27 resulting in the formation of the electron-deficient enone 30, which then participated in a Michael-type addition reaction with 1,3-dipolar 2-unsubstituted imidazole N-oxide 28 to provide the intermediate 31. In the last step, the final product 29 was

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• molecules through π–π stacking with the hydrophobic aromatic wall of the host. Finally, the boat was investigated as a catalyst for the Knoevenagel condensation reaction (Figure 2) of a series of aromatic aldehydes with 1,3-dimethylbarbituric acid and Meldrum’s acid in aqueous media. One of the primary

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• Meldrum’s acid in the presence of EDC·HCl and DMAP, followed by methanolysis of the corresponding adducts [27][28][31][36][37][38]. Reaction of the resulting β-keto esters 2a–h with N,N-dimethylformamide dimethylacetal afforded cycloaminyl β-enamino ketoesters 3a–h. After isolation of compounds 3a–h from

Synthesis of monophosphorylated lipid A precursors using 2-naphthylmethyl ether as a protecting group

• Jundi Xue,
• Ziyi Han,
• Gen Li,
• Khalisha A. Emmanuel,
• Cynthia L. McManus,
• Qiang Sui,
• Dongmian Ge,
• Qi Gao and
• Li Cai

Beilstein J. Org. Chem. 2020, 16, 1955–1962, doi:10.3762/bjoc.16.162

• (3) was treated with Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) followed by decarboxylation in methanol to give methyl 3-oxotetradecanoate (4) in 77% yield. The enantioselective hydrogenation of the β-carbonyl group using (R)-Ru(OAc)2(BINAP) at 65 °C and under 1.5 MPa H2 afforded methyl (R

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• ). Meldrum’s acid and its derivatives are versatile reagents in organic synthesis that can be transformed into a wide range of compounds. In 2006, the group of Fillion described the highly enantioselective synthesis of all-carbon benzylic quaternary stereocentres via a conjugate addition of dialkylzinc

• reagents to alkylidene Meldrum’s acids, resulting in the ACA products with high enantiopurity (Scheme 16) [47][48][49][50][51][52]. Different kinds of Meldrum’s acid derivatives were tolerated in this reaction, and the products could undergo various chemical transformations (Scheme 16A). Later on, this

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• triphenylphosphane with alkyl propiolates [9][10] or dialkyl acetylenedicarboxylates [11] and strong CH-acids, such as Meldrum’s acid, 1,3-dimethylbarbituric acid, dimedone and indane-1,3-dione, leads to stable 1,4-diionic phosphonium betaines I or II (Scheme 1) in high yields. An analogous reaction has been

• vinylphosphonium ion, and a proton transfer finally yields the 1,4-betaine. A kinetic study of the PPh3/DMAD/Meldrum’s acid reaction by spectrophotometric and stopped-flow methods has been published [14]. The initial 1,3-betaine has also been trapped with other electrophiles. The stable 1,4-betaines betaines III

• equivalents) was added to a solution of PPh3 and an active methylene compound 2a–c,e,f, a 1:1:1 three-component reaction occurred smoothly within 0.5–6 hours and yielded the phosphonium-1,5-betaines 3a–o in mostly high yields (Scheme 3 and Figure 1). Meldrum’s acid (2a), N,N’-dimethylbarbituric acid (2b), 1,3

Efficiency Eff_syn of complex syntheses as multicomponent reactions, its algorithm and calculations based on concrete criteria

• Heiner Eckert

Beilstein J. Org. Chem. 2019, 15, 1425–1433, doi:10.3762/bjoc.15.142

• total synthesis by Tietze uses a 4CR, specifically generated for this reaction from an aldehyde, meldrum’s acid, enol ether and methanol, as a key step in the synthesis to 4 (Scheme 6) [15]. This step-saving strategy for generating novel MCRs is a fast track towards the ubiquitous use of MCRs in complex

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• 01003, Ukraine A.V. Bogatsky physico-chemical institute of the National Academy of Sciences of Ukraine, 86, Lustdorfskaya doroga, 65080, Odessa, Ukraine 10.3762/bjoc.15.101 Abstract The unexpectedly uncatalyzed reaction between 2-amino-4-arylimidazoles, aromatic aldehydes and Meldrum’s acid has

• selectively led to the corresponding Knoevenagel–Michael adducts containing a free amino group in the imidazole fragment. The adducts derived from Meldrum’s acid have been smoothly converted into 1,7-diaryl-3-amino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-ones and 3-(2-amino-4-aryl-1H-imidazol-5-yl)-3

• considered as the analogues of both 3,3’-spirooxindole and 2-aminoimidazole marine sponge alkaloids. Keywords: 2-amino-4-arylimidazole; (2-amino-4-arylimidazolyl)propanoic acid; isatin; Meldrum’s acid; multicomponent reactions; pyrrolo[1,2-c]imidazole; 3,3’-spirooxindoles; Introduction Heterocyclic

One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

• Jun Ki Kim,
• Hwan Jung Lim,
• Kyung Chae Jeong and
• Seong Jun Park

Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16

• facile preparation of thienyl heterocycles 8. The mechanism for this reaction is based on the formation of a sulfur ylide-like intermediate. It was clearly suggested by (i) the intramolecular cyclization of ketene N,S-acetals 7 to the corresponding thiophenes 8, (ii) 1H NMR studies of Meldrum’s acid

• -substituted aminothioacetals 9, and (iii) substitution studies of the methoxy group on Meldrum’s acid containing N,S-acetals 9b. Notably, in terms of structural effects on the reactivity and stability of sulfur ylide-like intermediates, 2-pyridyl substituted compound 7a exhibited superior properties over

• ,S-acetals 9a–c since the X-ray crystal structure of Meldrum’s acid-based N,S-acetal was reported by Wentrup [84]. In addition, the intramolecular aldol condensation of Meldrum’s acids did not occur due to the ketone structures. Table 2 displays the 1H NMR result of the sulfur ylide-like intermediate

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds

• Alexey M. Starosotnikov,
• Dmitry V. Shkaev,
• Maxim A. Bastrakov,
• Ivan V. Fedyanin,
• Svyatoslav A. Shevelev and
• Igor L. Dalinger

Beilstein J. Org. Chem. 2017, 13, 2854–2861, doi:10.3762/bjoc.13.277

• the same time signals of diketonic form were found as traces. Meldrum’s acid and 1,3-dimethylbarbituric acid react with ANBF similarly in the absence of base to give compounds 10 and 11, respectively (Table 1, entries 5 and 6). 1H NMR spectra of these adducts in DMSO-d6 contain double sets of signals

Rh(II)-mediated domino [4 + 1]-annulation of α-cyanothioacetamides using diazoesters: A new entry for the synthesis of multisubstituted thiophenes

• Jury J. Medvedev,
• Ilya V. Efimov,
• Yuri M. Shafran,
• Vitaliy V. Suslonov,
• Vasiliy A. Bakulev and
• Valerij A. Nikolaev

Beilstein J. Org. Chem. 2017, 13, 2569–2576, doi:10.3762/bjoc.13.253

• thioamides 1a–e of cyanoacetic acid (differing in the structure of substituents in the amino fragment) and diazoesters of three types: acyclic diazomalonates 2a,b, their cyclic analogue, 5-diazo-2,2-dimethyl-1,3-dioxane-4,6-dione (diazo Meldrum’s acid, 2c), as well as α-cyanodiazoacetic ester 2d were used in

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

• Dmitry Yu. Vandyshev,
• Khidmet S. Shikhaliev,
• Andrey Yu. Potapov,
• Michael Yu. Krysin,
• Fedor I. Zubkov and
• Lyudmila V. Sapronova

Beilstein J. Org. Chem. 2017, 13, 2561–2568, doi:10.3762/bjoc.13.252

• good leaving groups [31][32] (Scheme 2). In the reactions of 1-aminoimidazoles with cyclic 1,3-dielectrophilic reagents (3-formylchromones [33], Meldrum’s acid derivatives [34], and N-arylmaleimides [35]), transformation of the structure of the latter ones is often observed (Scheme 3). Among these

Synergistic chiral iminium and palladium catalysis: Highly regio- and enantioselective [3 + 2] annulation reaction of 2-vinylcyclopropanes with enals

• Haipan Zhu,
• Peile Du,
• Jianjun Li,
• Ziyang Liao,
• Guohua Liu,
• Hao Li and
• Wei Wang

Beilstein J. Org. Chem. 2016, 12, 1340–1347, doi:10.3762/bjoc.12.127

• and methyl vinyl ketone and α,β-unsaturated esters [44]. Trost and co-workers orchestrated the only example of the enantioselective reaction of D–A cyclopropanes with C=C double bonds with Meldrum’s acid and alkylidenes or azlactone alkylidenes, catalyzed by the chiral Trost Pd(0)-complexes [45

• promote these processes (Table 1, entries 3–7). Inspired by Trost’s work of Pd(0)-catalyzed annulations of D–A cyclopropanes with C=C double bonds with Meldrum’s acid and alkylidenes or azlactone alkylidenes [45], we probed the Pd2(dba)3-dppe complex for the 1,4-addition cycloaddition reaction (Table 1

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• enantioselectivity as when the enantioselective conjugate addition was performed using α-substituted malononitriles (126e, Scheme 29) [57]. In a subsequent report, Lou and co-workers demonstrated that Meldrum’s acid derivatives 132b were also operative in the reduction–conjugate addition–enantioselective protonation

• ) [65]. Interestingly, the optimal organocatalyst for the transformation was chiral only at sulfur, when chiral amine motifs were explored, e.g., 1,2-cyclohexanediamine, poor enantioselectivity was observed (≤75:25 er). A variety of R1 substituents on Meldrum’s acid 156 were compatible with the reaction

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• , Fillion and co-workers studied the reactivity of Meldrum’s acid derivatives of the type 18 with regards to ACA reactions, using dialkylzinc as nucleophiles [17]. Employing the same catalytic system as Alexakis, namely Cu(OTf)2/(S,R,R)-L1, the reaction was also fully 1,6-selective, and its versatility was

• extended Michael acceptors. First applications of copper catalyzed 1,6-ACA in total synthesis. First example of enantioselective copper-catalyzed ACA on an extended Michael acceptor. Meldrum’s acid derivatives as substrates in enantioselective ACA. Reactivity of a cyclic dienone in Cu-catalyzed ACA of

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• steps with a 25% overall yield. The reaction started with methyl 2,5-dimethoxy-3-nitrobenzoate, which was reduced into the corresponding aniline under hydrogen conditions with palladium on carbon. The aniline was further treated with Meldrum’s acid and trimethyl orthoformate to afford an enamine which

• has an orange-red color. Synthesis of arnoamines A (40) and B (41) The synthesis of arnoamines A and B was accomplished in nine and ten steps in 13% and 4% overall yield, respectively. The reaction started with 2-methoxy-5-nitroaniline treated with Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• nitrate (40%, Scheme 56). Intramolecular Diels–Alder (DA) reaction: Suwa and co-workers [192] have synthesized the muscopyridine by a [4 + 2] cycloaddition of the bisketene 325. The condensation of acid dichloride derived from 323 with two molecules of Meldrum’s acid gave 324 which on thermal activation

A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids

• Johanna Trenner and
• Evgeny V. Prusov

Beilstein J. Org. Chem. 2015, 11, 323–327, doi:10.3762/bjoc.11.37

• ] variant of Lacey–Dieckmann [8] condensation (Scheme 1) [9][10]. Reaction of either β-ketoester 4 or Meldrum’s acid derivative 9 with suitably protected glycine esters (5,6,10), followed by base-induced condensation furnished the desired tetramic acid model compounds as crystalline solids after treatment

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

• László Tóth,
• Yan Fu,
• Hai Yan Zhang,
• Attila Mándi,
• Katalin E. Kövér,
• Tünde-Zita Illyés,
• Attila Kiss-Szikszai,
• Balázs Balogh,
• Tibor Kurtán,
• Sándor Antus and
• Péter Mátyus

Beilstein J. Org. Chem. 2014, 10, 2594–2602, doi:10.3762/bjoc.10.272

• reaction with 1,3-dimethylbarbituric acid (12) and Meldrum’s acid (13), the reaction with malonitrile (14) stopped at the stage of the Knoevenagel product rac-7c with MgSO4 in CHCl3 and further cyclization did not occur when heated in DMSO at 150 °C or refluxed in n-butanol. The NMR data of 7a,b clearly

• (−9.32), 221 (−11.60). trans-2,2-Dimethyl-11'-nitro-2'-phenyl-1',2'-dihydro-7b'H,9'H-spiro[1,3-dioxane-5,8'-quinolino[1,2-d][1,4]benzoxazepine]-4,6-dione (rac-trans-7b): To the stirred solution of rac-5 (100 mg, 0.27 mmol) in chloroform (5 mL), anhydrous MgSO4 (150 mg, 1.25 mmol) and Meldrum’s acid (54

• aromatic substitution by using 2-fluoro-5-nitrobenzaldehyde (11b) to give rac-5 containing a tertiary arylamine nitrogen in 71% yield. With the 2-chloro-5-nitrobenzaldehyde reagent, only 3% yield for rac-5 could be achieved. Subsequently rac-5 was reacted with 1,3-dimethylbarbituric acid (12), Meldrum’s

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• Knoevenagel condensation, the Michael addition, and the N-nucleophilic cyclization (Scheme 24) [94]. Whereas 5,5-dimethylcyclohexane-1,3-dione (66) or Meldrum’s acid (67) acted as the Knoevenagel donor, 3-methyl-1-phenyl-1H-pyrazol-5-amine (68) played the role of the Michael donor in these reactions. The

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• generality [20][21]. We found that an approach based upon direct acylation of methyl thioethers 8a,b (these were readily obtained from the required N-acylmethionine by DCC/DMAP coupling with Meldrum’s acid and cyclisation under reflux) was possible, which made use of the high acidity of the tetramate system

Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

• Aleksey I. Gerasyuto,
• Zhi-Xiong Ma,
• Grant S. Buchanan and
• Richard P. Hsung

Beilstein J. Org. Chem. 2013, 9, 1170–1178, doi:10.3762/bjoc.9.131

• by condensation with Meldrum’s acid in the presence of Ni(acac)2. Treatment of 23 with MeONa in MeOH under reflux gave vinylogous urethane 24. It is noteworthy that the geometry of the vinylogous urethane double bond exclusively favored Z, presumably due to the internal hydrogen bonding. Cleavage of