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Search for "three-component reaction" in Full Text gives 138 result(s) in Beilstein Journal of Organic Chemistry.
Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review
- Nosheen Beig,
- Varsha Goyal and
- Raj K. Bansal
Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102
- , generated from the tetranuclear complex, as the catalytically active species. 2.4 A3 reactions In recent years, the three component reaction of an aldehyde, a secondary amine and a terminal alkyne, known as A3 reaction to afford chiral propargylamines 140 has received much attention. The latter compounds
Graphical Abstract
Scheme 1: In situ generation of imidazolylidene carbene.
Scheme 2: Hg(II) complex of NHC.
Scheme 3: Isolable and bottlable carbene reported by Arduengo [3].
Scheme 4: First air-stable carbene synthesized by Arduengo in 1992 [5].
Figure 1: General structure of an NHC.
Figure 2: Stabilization of an NHC by donation of the lone pair electrons into the vacant p-orbital (LUMO) at ...
Figure 3: Abnormal NHC reported by Bertrand [8,9].
Figure 4: Cu(d) orbital to σ*C-N(NHC) interactions in NHC–CuX complexes computed at the B3LYP/def2-SVP level ...
Figure 5: Molecular orbital contributions to the NHC–metal bond.
Scheme 5: Synthesis of NHC–Cu(I) complexes by deprotonation of NHC precursors with a base.
Scheme 6: Synthesis of [NHC–CuX] complexes.
Scheme 7: Synthesis of [(ICy)CuX] and [(It-Bu)CuX] complexes.
Scheme 8: Synthesis of iodido-bridged copper–NHC complexes by deprotonation of benzimidazolium salts reported...
Scheme 9: Synthesis of copper complexes by deprotonation of triazolium salts.
Scheme 10: Synthesis of thiazolylidene–Cu(I) complex by deprotonation with KOt-Bu.
Scheme 11: Preparation of NHC–Cu(I) complexes.
Scheme 12: Synthesis of methylmalonic acid-derived anionic [(26a,b)CuCl]Li(THF)2 and zwitterionic (28) heterol...
Scheme 13: Synthesis of diaminocarbene and diamidocarbene (DAC)–Cu(I) complexes.
Scheme 14: Synthesis of the cationic (NHC)2Cu(I) complex 39 from benzimidazolium salts 38 with tetrakis(aceton...
Scheme 15: Synthesis of NHC and ADC (acyclic diamino carbenes) Cu(I) hexamethyldisilazide complexes reported b...
Scheme 16: Synthesis of NHC–copper(I) complexes using an acetylacetonate-functionalized imidazolium zwitterion...
Scheme 17: Synthesis of NHC–Cu(I) complexes through deprotonation of azolium salts with Cu2O.
Scheme 18: Synthesis of NHC–CuBr complex through deprotonation with Cu2O reported by Kolychev [31].
Scheme 19: Synthesis of chiral NHC–CuBr complexes from phenoxyimine-imidazolium salts reported by Douthwaite a...
Scheme 20: Preparation of linear neutral NHC–CuCl complexes through the use of Cu2O. For abbreviations, please...
Scheme 21: Synthesis of abnormal-NHC–copper(I) complexes by Bertrand, Cazin and co-workers [35].
Scheme 22: Microwave-assisted synthesis of thiazolylidene/benzothiazolylidene–CuBr complexes by Bansal and co-...
Scheme 23: Synthesis of NHC–CuX complexes through transmetallation.
Scheme 24: Preparation of six- or seven-membered NHC–Cu(I) complexes through transmetalation from Ag(I) comple...
Scheme 25: Synthesis of 1,2,3-triazolylidene–CuCl complexes through transmetallation of Ag(I) complexes genera...
Scheme 26: Synthesis of NHC–copper complexes having both Cu(I) and Cu(II) units through transmetalation report...
Scheme 27: Synthesis of new [(IPr(CH2)3Si(OiPr)3)CuX] complexes and anchoring on MCM-41.
Scheme 28: Synthesis of bis(trimethylsilyl)phosphide–Cu(I)–NHC complexes through ligand displacement.
Scheme 29: Synthesis of silyl- and stannyl [(NHC)Cu−ER3] complexes.
Scheme 30: Synthesis of amido-, phenolato-, thiophenolato–Cu(NHC) complexes.
Scheme 31: Synthesis of first isolable NHC–Cu–difluoromethyl complexes reported by Sanford et al. [44].
Scheme 32: Synthesis of NHC–Cu(I)–bifluoride complexes reported by Riant, Leyssens and co-workers [45].
Scheme 33: Conjugate addition of Et2Zn to enones catalyzed by an NHC–Cu(I) complex reported by Woodward in 200...
Scheme 34: Hydrosilylation of a carbonyl group.
Scheme 35: NHC–Cu(I)-catalyzed hydrosilylation of ketones reported by Nolan et al. [48,49].
Scheme 36: Application of chiral NHC–CuCl complex 104 for the enantioselective hydrosilylation of ketones.
Scheme 37: Hydrosilylation reactions catalyzed by NHC–Cu(Ot-Bu) complexes.
Scheme 38: NHC–CuCl catalyzed carbonylative silylation of alkyl halides.
Scheme 39: Nucleophilic conjugate addition to an activated C=C bond.
Figure 6: Molecular electrostatic potential maps (MESP) of two NHC–CuX complexes computed at the B3LYP/def2-S...
Scheme 40: Conjugate addition of Grignard reagents to 3-alkyl-substituted cyclohexenones catalyzed by a chiral...
Scheme 41: NHC–copper complex-catalyzed conjugate addition of Grignard reagent to 3-substituted hexenone repor...
Scheme 42: Conjugate addition or organoaluminum reagents to β-substituted cyclic enones.
Scheme 43: Conjugate addition of boronates to acyclic α,β-unsaturated carboxylic esters, ketones, and thioeste...
Scheme 44: NHC–Cu(I)-catalyzed hydroboration of an allene reported by Hoveyda [63].
Scheme 45: Conjugate addition of Et2Zn to cyclohexenone catalyzed by NHC–Cu(I) complex derived from benzimidaz...
Scheme 46: Asymmetric conjugate addition of diethylzinc to 3-nonen-2-one catalyzed by NHC–Cu complexes derived...
Scheme 47: General scheme of a [3 + 2] cycloaddition reaction.
Scheme 48: [3 + 2] Cycloaddition of azides with alkynes catalyzed by NHC–Cu(I) complexes reported by Diez-Gonz...
Scheme 49: Application of NHC–CuCl/N-donor combination to catalyze the [3 + 2] cycloaddition of benzyl azide w...
Scheme 50: [3 + 2] Cycloaddition of azides with acetylenes catalyzed by bis(NHC)–Cu complex 131 and mixed NHC–...
Figure 7: NHC–CuCl complex 133 as catalyst for the [3 + 2] cycloaddition of alkynes with azides at room tempe...
Scheme 51: [3 + 2] Cycloaddition of a bulky azide with an alkynylpyridine using [(NHC)Cu(μ-I)2Cu(NHC)] copper ...
Scheme 52: [3 + 2] Cycloaddition of benzyl azide with phenylacetylene under homogeneous and heterogeneous cata...
Scheme 53: [3 + 2] Cycloaddition of benzyl azide with acetylenes catalyzed by bisthiazolylidene dicopper(I) co...
Figure 8: Copper (I)–NHC linear coordination polymer 137 and its conversion into tetranuclear (138) and dinuc...
Scheme 54: An A3 reaction.
Scheme 55: Synthesis of SiO2-immobilized NHC–Cu(I) catalyst 141 and its application in the A3-coupling reactio...
Scheme 56: Preparation of dual-purpose Ru@SiO2–[(NHC)CuCl] catalyst system 142 developed by Bordet, Leitner an...
Scheme 57: Application of the catalyst system Ru@SiO2–[Cu(NHC)] 142 to the one-pot tandem A3 reaction and hydr...
Scheme 58: A3 reaction of phenylacetylene with secondary amines and aldehydes catalyzed by benzothiazolylidene...
Figure 9: Kohn–Sham HOMOs of phenylacetylene and NHC–Cu(I)–phenylacetylene complex computed at the B3LYP/def2...
Figure 10: Energies of the FMOs of phenylacetylene, iminium ion, and NHC–Cu(I)–phenylacetylene complex compute...
Scheme 59: NHC–Cu(I) catalyzed diboration of ketones 147 by reacting with bis(pinacolato)diboron (148) reporte...
Scheme 60: Protoboration of terminal allenes catalyzed by NHC–Cu(I) complexes reported by Hoveyda and co-worke...
Scheme 61: NHC–CuCl-catalyzed borylation of α-alkoxyallenes to give 2-boryl-1,3-butadienes.
Scheme 62: Regioselective hydroborylation of propargylic alcohols and ethers catalyzed by NHC–CuCl complexes 1...
Scheme 63: NHC–CuOt-Bu-catalyzed semihydrogenation and hydroborylation of alkynes.
Scheme 64: Enantioselective NHC–Cu(I)-catalyzed hydroborations of 1,1-disubstituted aryl olefins reported by H...
Scheme 65: Enantioselective NHC–Cu(I)-catalyzed hydroboration of exocyclic 1,1-disubstituted alkenes reported ...
Scheme 66: Markovnikov-selective NHC–CuOH-catalyzed hydroboration of alkenes and alkynes reported by Jones et ...
Scheme 67: Dehydrogenative borylation and silylation of styrenes catalyzed by NHC–CuOt-Bu complexes developed ...
Scheme 68: N–H/C(sp2)–H carboxylation catalyzed by NHC–CuOH complexes.
Scheme 69: C–H Carboxylation of benzoxazole and benzothiazole derivatives with CO2 using a 1,2,3-triazol-5-yli...
Scheme 70: Use of Cu(I) complex derived from diethylene glycol-functionalized imidazo[1,5,a] pyridin-3-ylidene...
Scheme 71: Allylation and alkenylation of polyfluoroarenes and heteroarenes catalyzed by NHC–Cu(I) complexes r...
Scheme 72: Enantioselective C(sp2)–H allylation of (benz)oxazoles and benzothiazoles with γ,γ-disubstituted pr...
Scheme 73: C(sp2)–H arylation of arenes catalyzed by dual NHC–Cu/NHC–Pd catalytic system.
Scheme 74: C(sp2)–H Amidation of (hetero)arenes with N-chlorocarbamates/N-chloro-N-sodiocarbamates catalyzed b...
Scheme 75: NHC–CuI catalyzed thiolation of benzothiazoles and benzoxazoles.
Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction
- Ziying Xiao,
- Fengshun Xu,
- Jing Sun and
- Chao-Guo Yan
Beilstein J. Org. Chem. 2023, 19, 1234–1242, doi:10.3762/bjoc.19.91
- -promoted three-component reaction of ammonium acetate, isatins and in situ-generated 3-isatyl-1,4-dicarbonyl compounds. The piperidine-promoted three-component reaction of ammonium acetate, isatins and the in situ-generated dimedone adducts of 3-ethoxycarbonylmethyleneoxindoles afforded mutlifunctionalized
- -oxoindolin-3-ylidene)acetate in toluene according to the published method [52]. Then, the reaction conditions of the three-component reaction of isatyl adduct 1a (0.20 mmol), isatin 2a (0.20 mmol) and ammonium acetate (0.5 mmol) were examined according to Zhang and co-workers reported reaction (reaction 1 in
- ). Prolonging the reaction time did not increase the yield of product 3a (Table 1, entry 12). Therefore, the optimized reaction conditions found for this three-component reaction are the use of a mixture of methanol and toluene at 50 °C for seven hours in the presence of piperidine. With the optimized reaction
Graphical Abstract
Scheme 1: Representative cascade reactions of Michael adducts of 3-methyleneoxindoles.
Figure 1: Crystal structure of dispiro compound 3a.
Figure 2: Crystal structure of compound 4a.
Scheme 2: Proposed reaction mechanism.
The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition
- Xiu-Yu Chen,
- Hui Zheng,
- Ying Han,
- Jing Sun and
- Chao-Guo Yan
Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73
- Xiu-Yu Chen Hui Zheng Ying Han Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Jiangsu, Yangzhou 225002, China 10.3762/bjoc.19.73 Abstract The three-component reaction of isoquinolines, dialkyl acetylenedicarboxylates, and 5,6-unsubstituted 1,4
- ][28][29][30]. The 5,6-unsubstituted 1,4-dihydropyridines can be easily prepared from the three-component reaction of an arylamine, cinnamaldehyde, and methyl acetoacetate [31][32][33][34]. The unsubstituted C=C double bond in 5,6-unsubstituted 1,4-dihydropyridines exhibits high reactivity and could
- act as activated alkene to take part in various cycloaddition reactions [35][36][37][38][39][40]. For example, Lavilla and co-workers developed a Sc(OTf)3-catalyzed three-component reaction of 5,6-unsubstituted 1,4-dihydropyridines, arylamines and ethyl glyoxylate for the preparation of various pyrido
Graphical Abstract
Scheme 1: Various cycloaddition reactions of 5,6-unsymmetric 1,4-dihydropyridines.
Figure 1: Single crystal structure of the compound 4k.
Figure 2: Single crystal structure of compound 5a.
Figure 3: Single crystal structure of compound 6f.
Scheme 2: Plausible reaction mechanism for the various products 4, 5, and 6.
Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions
- Oleksandr V. Kolomiiets,
- Alexander V. Tsygankov,
- Maryna N. Kornet,
- Aleksander A. Brazhko,
- Vladimir I. Musatov and
- Valentyn A. Chebanov
Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53
- heterocyclic acid 8a was obtained by a three-component reaction of 2-amino-5-chloropyridine (1a), 4-formylbenzoic acid (5f), and tert-butyl isocyanide (3a) according to the procedure described above (Scheme 3). In another step, we attempted to introduce the acid 8a into the Ugi four-component reaction with 4
Graphical Abstract
Scheme 1: Diversity of structures synthesized by combining IMCR’s.
Figure 1: Drugs possessing imidazo[1,2-a]pyridine unit.
Figure 2: Drugs possessing peptide unit.
Scheme 2: Diversity of GBB reaction products as precursors for Ugi reaction.
Scheme 3: Synthesis of new acids containing a substituted imidazo[1,2-a]pyridine fragment.
Scheme 4: Synthesis of new peptidomimetics containing a substituted imidazo[1,2-a]pyridine fragment.
Scheme 5: Synthesis and reactivity of new acids containing a substituted imidazo[1,2-a]pyridine fragment with...
Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates
- Bastian Jakob,
- Nico Schneider,
- Luca Gengenbach and
- Georg Manolikakes
Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52
- Bastian Jakob Nico Schneider Luca Gengenbach Georg Manolikakes Department of Chemistry, RPTU Kaiserslautern-Landau, Erwin-Schrödinger-Str. Geb. 54, D-67663 Kaiserslautern, Germany 10.3762/bjoc.19.52 Abstract A palladium-catalyzed enantioselective three-component reaction of glyoxylic acid
- vs 89% after 2 h with PhB(OH)2). These preliminary studies confirmed our initial hypothesis that aryltrifluoroborates can be utilized as precursors for a slow release of the free boronic acid in our palladium-catalyzed three-component reaction. Therefore, we started to optimize the reaction
- corresponding R,R-iPrBox-ligand the second enantiomer, (R)-arylglycine 10l could be prepared with a similar yield and enantioselectivity. Conclusion In summary, we have reported a palladium-catalyzed enantioselective three-component reaction of aryltrifluoroborates, sulfonamides, and glyoxylic acid. This method
Graphical Abstract
Figure 1: Biologically active molecules containing α-arylglycine motifs (highlighted in green and blue).
Scheme 1: The Petasis reaction – fundamental reactivities and recent developments.
Scheme 2: Observations from previous studies and mechanistic rationale.
Scheme 3: Initial experiments.
Scheme 4: Reaction scope – aryltrifluoroborates (yields and enantiomeric ratios in parentheses refer to our p...
Scheme 5: Synthesis of both enantiomers of arylglycine building block 18.
An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides
- Shubham Sharma,
- Dharmender Singh,
- Sunit Kumar,
- Vaishali,
- Rahul Jamra,
- Naveen Banyal,
- Deepika,
- Chandi C. Malakar and
- Virender Singh
Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22
- -tethered thioamide and amide conjugates. The thioamides were generated by employing a three-component reaction of diverse pyrazole C-3/4/5 carbaldehydes, secondary amines, and elemental sulfur in a single synthetic operation. The advantages of this developed protocol refer to the broad substrate scope
Graphical Abstract
Figure 1: Representative drug molecules based on pyrazole, thioamide, and amide derivatives.
Figure 2: Previous and present findings for the synthesis of thioamide derivatives.
Scheme 1: Synthesis of pyrazole C-3-tethered thioamides.
Scheme 2: Synthesis of pyrazole C-4-tethered thioamides.
Scheme 3: Metal- and catalyst-free preparation of pyrazole C-5-linked thioamide conjugates.
Scheme 4: Synthesis of 4-iodopyrazole C-3-tethered thioamides.
Scheme 5: Gram-scale scope of the current protocol.
Scheme 6: Control experiment.
Scheme 7: H2O2-mediated synthesis of pyrazole-pyridine conjugates with amide tethers.
Scheme 8: Synthesis of pyrazole-pyridine conjugates 9F and 10F having amide tethers.
Scheme 9: A tentative mechanism for the formation of pyrazole conjugates with thioamide and amide linkage.
A novel bis-triazole scaffold accessed via two tandem [3 + 2] cycloaddition events including an uncatalyzed, room temperature azide–alkyne click reaction
- Ksenia Malkova,
- Andrey Bubyrev,
- Vasilisa Krivovicheva,
- Dmitry Dar’in,
- Alexander Bunev and
- Mikhail Krasavin
Beilstein J. Org. Chem. 2022, 18, 1636–1641, doi:10.3762/bjoc.18.175
- University, Kaliningrad 236016, Russian Federation 10.3762/bjoc.18.175 Abstract The previously described α-acetyl-α-diazomethanesulfonamide was employed in a three-component reaction with azide-containing benzaldehydes and propargylamines. Besides the initial formation of the triazole core, the reaction
- scaffolds. Recently, we reported a novel, metal-free synthesis of 1,5-disubstituted 1,2,3-triazoles via a three-component reaction of α-acetyl-α-diazomethanesulfonamide (1) with aldehydes and amines [4]. The reaction proceeded, presumably, through the formation of the initial 1,2,3-triazoline adduct 2 [5
- on cell proliferation in concentrations up to 250 μM. This validates these novel compounds as non-cytotoxic probes for interrogation of various biological targets. Conclusion The previously described α-acetyl-α-diazomethanesulfonamide was employed in a three-component reaction with azide-containing
Graphical Abstract
Figure 1: (a) Previously developed three-component approach to 1,5-disubstituted 1,2,3-triazoles; (b) double ...
Scheme 1: Results of a trial reaction between 1, o-azidobenzaldehyde (3a) and propargylamine.
Figure 2: Diversely bioactive compounds based on scaffolds A and B.
Scheme 2: Three-component reaction of 1, propargylamine and various o-azidobenzaldehydes.
Figure 3: Aromatic azido aldehydes 3j–l that failed to react with 1 and propargylamine.
Scheme 3: Variations of the amine component in the reactions with 1 and 3a.
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
- through C–H/C–H coupling [10]. Also, in 2020, Valery P. Perevalov and team reported a three-component reaction of 2-unsubstituted imidazole N-oxides, arylglyoxals, and CH-acids [11]. However, the use of imidazole 1-oxides is not much unfolded till now among the science community. There were quite some
- arylglyoxals to investigate the scope of substrates. No products were obtained in case of the acyclic CH-acids like dimethyl malonate, acetylacetone, and ethyl acetoacetate under the same conditions. The reaction follows almost the same mechanistic pathway that was previously mentioned as three-component
- reaction. However, in this reaction process, 2.0 equiv of CH-acids were needed against arylglyoxals since the electrophilic character of glyoxals is higher than that of aldehydes, generating less stable enones while reacting with CH-acids. First, 1.0 equiv CH-acid was reacted with 1.0 equiv arylglyoxal to
Graphical Abstract
Figure 1: Selected imidazole-based bioactive molecules.
Scheme 1: Formation of ethyl 2-cyano-2-(1,3-dihydro-2H-imidazole-2-ylidene)acetate derivatives via [3 + 2] cy...
Scheme 2: C–H/C–Li coupling reaction of 2H-imidazole 1-oxides with pentafluorophenyllithium.
Scheme 3: Transition-metal-free coupling reaction of 2H-imidazole 1-oxides with polyphenols. Reaction conditi...
Scheme 4: Halogenation reaction of 2-unsubstituted imidazole N-oxides using tosyl halogenides.
Scheme 5: Solvent-free chlorination reaction of imidazole N-oxides.
Scheme 6: Multicomponent reaction of imidazole N-oxides 28 with Meldrum’s acid (26) and aldehydes.
Scheme 7: Multicomponent reaction of imidazole N-oxides with CH-acids and aldehydes. Reaction conditions: aTh...
Scheme 8: Three-component condensation reaction of imidazole N-oxides, arylglyoxals, and CH-acids 38 (dimedon...
Scheme 9: Synthesis of imidazole-2-thiones containing cyclohexyl-substituents at 3-position.
Scheme 10: Preparation of optically active derivatives of 3-butoxyimidazole-2-thione.
Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones
- Nguyen Tran Nguyen,
- Vo Viet Dai,
- Nguyen Ngoc Tri,
- Luc Van Meervelt,
- Nguyen Tien Trung and
- Wim Dehaen
Beilstein J. Org. Chem. 2022, 18, 1140–1153, doi:10.3762/bjoc.18.118
- aromatic aldehyde, aniline, and ethyl 2,4-dioxovalerate, respectively, in acetic acid as solvent was used to synthesize other substituted 4-acetyl-3-hydroxy-3-pyrroline-2-ones. It may be surmised that the first step in the three-component reaction to synthesize substituted 4-acetyl-3-hydroxy-3-pyrroline-2
- shown in solvent models used in this work. Conclusion 4-Acetyl-3-hydroxy-3-pyrrolin-2-ones were synthesized successfully via the three-component reaction of an aromatic aldehyde, aniline, and ethyl 2,4-dioxovalerate with acceptable yields. The broadening of peaks in the 13C NMR spectra for the two
- -component reaction. Proposed mechanistic path for the synthesis of substituted 4-acetyl-3-hydroxy-3-pyrroline-2-ones. Tautomerism of compounds 4a–c in DMSO. Reaction pathways from 4a, 4a’ to 10ab via IS5 in the gase phase. Reaction pathways from 4a to 10ab-v2 via IS3 in the gase phase. Starting materials 1a
Graphical Abstract
Figure 1: Structure of naturally occurring and synthetic 2-pyrrolidone derivatives.
Figure 2: Structure of natural compounds containing a 1,5-dihydro-2H-pyrrol-2-one subunit.
Scheme 1: Synthesis of substituted 4-acetyl-3-hydroxy-3-pyrroline-2-ones 4 via three-component reaction.
Scheme 2: Proposed mechanistic path for the synthesis of substituted 4-acetyl-3-hydroxy-3-pyrroline-2-ones.
Scheme 3: Tautomerism of compounds 4a–c in DMSO.
Figure 3: View of the molecular structure of compound 10aa with atom labeling. Displacement ellipsoids are dr...
Figure 4: The PES of reaction for the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-dione 10ab enamine de...
Scheme 4: Reaction pathways from 4a, 4a’ to 10ab via IS5 in the gase phase.
Scheme 5: Reaction pathways from 4a to 10ab-v2 via IS3 in the gase phase.
Figure 5: The PES for the possible pathways (1), (2), (3), and (4) in ethanol solvent.
Figure 6: The optimized structures of some reactants, intermediates, transition states, and products in the p...
Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates
- Hui Zheng,
- Ying Han,
- Jing Sun and
- Chao-Guo Yan
Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99
- remained in the product 3a. This result might be due to the weak basic system and the milder conditions. An attempt to develop a three-component reaction by directly using the phenacyl bromide and malononitrile to replace the previously prepared phenacylmalononitrile in the reaction was not successful. The
Graphical Abstract
Scheme 1: Representative cycloaddition reactions of phenacylmalononitriles.
Figure 1: Single crystal structure of compound 3k.
Figure 2: Single crystal structure of compound 4a.
Figure 3: Single crystal structure of compound 4c.
Scheme 2: Proposed reaction mechanism for compounds 3, 4, and 5.
Figure 4: Single crystal structure of compound 5.
Scheme 3: Control experiment.
Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes
- Mio Matsumura,
- Kaho Tsukada,
- Kiwa Sugimoto,
- Yuki Murata and
- Shuji Yasuike
Beilstein J. Org. Chem. 2022, 18, 863–871, doi:10.3762/bjoc.18.87
- attention [15][19][20][21][22][23][24][25][26]. This method involves a transition-metal-catalyzed one-pot, three-component reaction in which two functional groups are simultaneously introduced on the Se atom via double selenation. As examples, the following Cu-catalyzed one-pot reactions have been reported
Graphical Abstract
Figure 1: Biologically active selenides having alkynyl or imidazopyridinyl groups.
Figure 2: (a) ORTEP drawing of 4aa and (b) its stacking structure.
Scheme 1: Control reactions.
Figure 3: Proposed mechanism.
Scheme 2: Transformation from 4aa.
Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles
- Shao-Cong Zhan,
- Ren-Jie Fang,
- Jing Sun and
- Chao-Guo Yan
Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80
- this respect, Lévy reported a copper-catalyzed three-component reaction of aromatic aldehydes, ethyl indole-2-acetate and N-alkylmaleimides for the efficient construction of polycyclic tetrahydrocarbazoles, in which indolo-2,3-quinodimethane intermediate was initially generated and sequentially
- chemistry. Recently, we have reported the efficient construction of a series of heterocyclic spiro compounds including tetrahydrospiro[carbazole-3,3’-indolines] by using the Levy three-component reaction of indole-2-acetate, aromatic aldehydes and various cyclic dienophiles such as 3-phenacylideneoxindoles
- benzoyl group and the phenyl group in oxindole stand in cis-position in the starting 3-phenacylideneoxindoles [75]. Therefore, a concerted Diels–Alder reaction should be involved in this three-component reaction. On the basis of this success, we further considered whether other dienophiles could be
Graphical Abstract
Scheme 1: Construction of diverse tetrahydrocarbazoles via Levy-type reaction.
Scheme 2: Synthesis of spiro[carbazole-3,3'-inolines]. Reaction conditions: 2-methylindole (0.5 mmol), aromat...
Scheme 3: Synthesis of spiro[carbazole-2,3'-indolines]. Reaction conditions: 2-methylindole (0.5 mmol), aroma...
Scheme 4: Synthesis of tetrahydrospiro[carbazole-3,5'-pyrimidines]. Reaction conditions: 2-methylindole (0.5 ...
Scheme 5: Synthesis of tetrahydrospiro[carbazole-3,1'-cycloalkane]-diones. Reaction conditions: 2-methylindol...
Scheme 6: Synthesis of 3,3'-(arylmethylene)bis(2-methyl-1H-indole). Reaction conditions: 2-methylindole (1.0 ...
Scheme 7: Proposed reaction mechanism for the multicomponent reaction.
Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies
- Conrad Kuhwald,
- Sibel Türkhan and
- Andreas Kirschning
Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70
- technologies microwave and flow were combined are the Dimroth rearrangement exemplified for the conversion of 1,3-thiazine 3 to the corresponding 3-substituted hydropyrimidine 4 (Scheme 7, reaction 1) [48]. A noteworthy example was recently published by Organ and co-workers [49]. A three-component reaction of
- three-component reaction (reaction 2) to propargyl amines 8 under continuous flow conditions with microwave assistance. Claisen rearrangement in flow: A. comparison between conventional heating (external oil bath), microwave irradiation, and inductive heating; and B. coupled flow-through protocol
Graphical Abstract
Figure 1: Inductive heating, a powerful tool in industry and the Life Sciences.
Figure 2: Electric displacement field of a ferromagnetic and superparamagnetic material.
Figure 3: Temperature profiles of reactors heated conventionally and by RF heating (Figure 3 redrawn from [24]).
Scheme 1: Continuous flow synthesis of isopulegol (2) from citronellal (1).
Scheme 2: Dry (reaction 1) and steam (reaction 2) methane reforming.
Scheme 3: Calcination and RF heating.
Scheme 4: The continuously operated “Sabatier” process.
Scheme 5: Biofuel production from biomass using inductive heating for pyrolysis.
Scheme 6: Water electrolysis using an inductively heated electrolysis cell.
Scheme 7: Dimroth rearrangement (reaction 1) and three-component reaction (reaction 2) to propargyl amines 8 ...
Figure 4: A. Flow reactor filled with magnetic nanostructured particles (MagSilicaTM) and packed bed reactor ...
Scheme 8: Claisen rearrangement in flow: A. comparison between conventional heating (external oil bath), micr...
Scheme 9: Continuous flow reactions and comparison with batch reaction (oil bath). A. Pd-catalyzed transfer h...
Scheme 10: Continuous flow reactions and comparison with batch reaction (oil bath). A. pericyclic reactions an...
Scheme 11: Reactions under flow conditions using inductively heated fixed-bed materials serving as stoichiomet...
Scheme 12: Reactions under flow conditions using inductively heated fixed-bed materials serving as catalysts: ...
Scheme 13: Two step flow protocol for the preparation of 1,1'-diarylalkanes 77 from ketones and aldehydes 74, ...
Scheme 14: O-Alkylation, the last step in the multistep flow synthesis of Iloperidone (80) accompanied with a ...
Scheme 15: Continuous two-step flow process consisting of Grignard reaction followed by water elimination bein...
Scheme 16: Inductively heated continuous flow protocol for the synthesis of Iso E Super (88) [91,92].
Scheme 17: Three-step continuous flow synthesis of macrocycles 89 and 90 with musk-like olfactoric properties.
Bifunctional thiourea-catalyzed asymmetric [3 + 2] annulation reactions of 2-isothiocyanato-1-indanones with barbiturate-based olefins
- Jiang-Song Zhai and
- Da-Ming Du
Beilstein J. Org. Chem. 2022, 18, 25–36, doi:10.3762/bjoc.18.3
- through a gram-scale synthesis, one-pot three-component reactions and further transformation experiments of the products. Keywords: asymmetric catalysis; cyclization reaction; Michael addition; one-pot three-component reaction; spirobarbiturates; Introduction Indane scaffolds exist in various
- % ee) could still be maintained (Scheme 6b). This one-pot three-component reaction would be more convenient for potential industrial applications. Finally, in order to understand the enantioselective formation process of product 3, we proposed the possible mechanisms for the [3 + 2] cyclization
- residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 4:1) to give pure compound 5 as white solid (44.0 mg, 95% yield). 6. One-pot three-component reaction for the synthesis of 3aa 1,3-Dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (15.6 mg, 0.10 mmol) and
Graphical Abstract
Figure 1: Selected examples of natural products and drugs possessing the indane scaffold.
Scheme 1: Known strategies and conceptual advance of this contribution.
Figure 2: Selected examples of bioactive spirobarbiturates.
Figure 3: The screened organocatalysts.
Scheme 2: Substrate scope of 2-isothiocyanato-1-indanones. The reactions were carried out with 1 (0.12 mmol), ...
Scheme 3: Substrate scope of barbiturate-based olefins. The reactions were carried out with 1a (0.12 mmol), 2...
Figure 4: X-ray crystal structure of 3ae (displacement ellipsoids are drawn at the 50% probability level).
Scheme 4: Gram-scale synthesis of 3ah.
Scheme 5: Further transformation of 3ah.
Scheme 6: One-pot three-component reaction.
Scheme 7: Proposed reaction mechanism.
Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure
- Agnieszka Grajewska,
- Maria Chrzanowska and
- Wiktoria Adamska
Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168
- Petasis three-component reaction followed by the Pomeranz–Fritsch–Bobbitt cyclization. The Petasis reaction between boronic acids, carbonyl derivatives, and amines, leading to the formation of amino acids and the Pomeranz–Fritsch–Bobbitt cyclization of amino acetals, leading to the construction of C-1
Graphical Abstract
Figure 1: Natural isopavine alkaloids and synthetic derivatives of isopavine.
Figure 2: The structure and numbering of dihydromethanodibenzoazocine.
Scheme 1: The Petasis reaction and the Pomeranz–Fritsch–Bobbitt cyclization.
Scheme 2: The synthesis of 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids via a combination ...
Scheme 3: Synthesis of N-benzylated aminoacetaldehyde acetals 3a–e. Conditions: a) reaction run in EtOH; b) r...
Scheme 4: Synthesis of amino acids 6a–g.
Scheme 5: Synthesis of dihydromethanodibenzoazocine-5-carboxylic acids 7a–f. Conditions: a) 20% HCl, rt, 24 h...
Scheme 6: Synthesis of TA-073.
Scheme 7: Reaction of 6a with 4% aqueous HCl solution in THF and with 20% aqueous HCl solution. Conditions: a...
Scheme 8: Three pathways of the synthesis of 12, the decarboxylated analogue of 6a.
Scheme 9: The chemical behavior of 12 in 4% aqueous HCl solution in THF and in 20% aqueous HCl solution.
Scheme 10: A plausible mechanism of the reaction of 6a with 4% aqueous HCl solution in THF.
Photoredox catalysis in nickel-catalyzed C–H functionalization
- Lusina Mantry,
- Rajaram Maayuri,
- Vikash Kumar and
- Parthasarathy Gandeepan
Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143
- [141] independently demonstrated photoredox/nickel-catalyzed approaches to olefin difunctionalizations involving C(sp3)–H activation. Thus, Kong devised a synthetic method combining nickel catalysis with tetrabutylammonium decatungstate (TBADT) as photocatalyst for the three component reaction of
Graphical Abstract
Scheme 1: Nickel-catalyzed cross-coupling versus C‒H activation.
Figure 1: Oxidative and reductive quenching cycles of a photocatalyst. [PC] = photocatalyst, A = acceptor, D ...
Scheme 2: Photoredox nickel-catalyzed C(sp3)–H arylation of dimethylaniline (1a).
Scheme 3: Photoredox nickel-catalyzed arylation of α-amino, α-oxy and benzylic C(sp3)‒H bonds with aryl bromi...
Figure 2: Proposed catalytic cycle for the photoredox-mediated HAT and nickel catalysis enabled C(sp3)‒H aryl...
Scheme 4: Photoredox arylation of α-amino C(sp3)‒H bonds with aryl iodides.
Figure 3: Proposed mechanism for photoredox nickel-catalyzed α-amino C‒H arylation with aryl iodides.
Scheme 5: Nickel-catalyzed α-oxy C(sp3)−H arylation of cyclic and acyclic ethers.
Figure 4: Proposed catalytic cycle for the C(sp3)−H arylation of cyclic and acyclic ethers.
Scheme 6: Photochemical nickel-catalyzed C–H arylation of ethers.
Figure 5: Proposed catalytic cycle for the nickel-catalyzed arylation of ethers with aryl bromides.
Scheme 7: Nickel-catalyzed α-amino C(sp3)‒H arylation with aryl tosylates.
Scheme 8: Arylation of α-amino C(sp3)‒H bonds by in situ generated aryl tosylates from phenols.
Scheme 9: Formylation of aryl chlorides through redox-neutral 2-functionalization of 1,3-dioxolane (13).
Scheme 10: Photochemical C(sp3)–H arylation via a dual polyoxometalate HAT and nickel catalytic manifold.
Figure 6: Proposed mechanism for C(sp3)–H arylation through dual polyoxometalate HAT and nickel catalytic man...
Scheme 11: Photochemical nickel-catalyzed α-hydroxy C‒H arylation.
Scheme 12: Photochemical synthesis of fluoxetine (21).
Scheme 13: Photochemical nickel-catalyzed allylic C(sp3)‒H arylation with aryl bromides.
Figure 7: Proposed mechanism for the photochemical nickel-catalyzed allylic C(sp3)‒H arylation with aryl brom...
Scheme 14: Photochemical C(sp3)‒H arylation by the synergy of ketone HAT catalysis and nickel catalysis.
Figure 8: Proposed mechanism for photochemical C(sp3)‒H arylation by the synergy of ketone HAT catalysis and ...
Scheme 15: Benzophenone- and nickel-catalyzed photoredox benzylic C–H arylation.
Scheme 16: Benzaldehyde- and nickel-catalyzed photoredox C(sp3)–H arylation.
Scheme 17: Photoredox and nickel-catalyzed enantioselective benzylic C–H arylation.
Figure 9: Proposed mechanism for the photoredox and nickel-catalyzed enantioselective benzylic C–H arylation.
Scheme 18: Photoredox nickel-catalyzed α-(sp3)‒H arylation of secondary benzamides with aryl bromides.
Scheme 19: Enantioselective sp3 α-arylation of benzamides.
Scheme 20: Nickel-catalyzed decarboxylative vinylation/C‒H arylation of cyclic oxalates.
Figure 10: Proposed mechanism for the nickel-catalyzed decarboxylative vinylation/C‒H arylation of cyclic oxal...
Scheme 21: C(sp3)−H arylation of bioactive molecules using mpg-CN photocatalysis and nickel catalysis.
Figure 11: Proposed mechanism for the mpg-CN/nickel photocatalytic C(sp3)–H arylation.
Scheme 22: Nickel-catalyzed synthesis of 1,1-diarylalkanes from alkyl bromides and aryl bromides.
Figure 12: Proposed mechanism for photoredox nickel-catalyzed C(sp3)–H alkylation via polarity-matched HAT.
Scheme 23: Photoredox nickel-catalyzed C(sp3)‒H alkylation via polarity-matched HAT.
Scheme 24: Benzaldehyde- and nickel-catalyzed photoredox C(sp3)‒H alkylation of ethers.
Scheme 25: Benzaldehyde- and nickel-catalyzed photoredox C(sp3)‒H alkylation of amides and thioethers.
Scheme 26: Photoredox and nickel-catalyzed C(sp3)‒H alkylation of benzamides with alkyl bromides.
Scheme 27: CzIPN and nickel-catalyzed C(sp3)‒H alkylation of ethers with alkyl bromides.
Figure 13: Proposed mechanism for the CzIPN and nickel-catalyzed C(sp3)‒H alkylation of ethers.
Scheme 28: Nickel/photoredox-catalyzed methylation of (hetero)aryl chlorides and acid chlorides using trimethy...
Figure 14: Proposed catalytic cycle for the nickel/photoredox-catalyzed methylation of (hetero)aryl chlorides ...
Scheme 29: Photochemical nickel-catalyzed C(sp3)–H methylations.
Scheme 30: Photoredox nickel catalysis-enabled alkylation of unactivated C(sp3)–H bonds with alkyl bromides.
Scheme 31: Photochemical C(sp3)–H alkenylation with alkenyl tosylates.
Scheme 32: Photoredox nickel-catalyzed hydroalkylation of internal alkynes.
Figure 15: Proposed mechanism for the photoredox nickel-catalyzed hydroalkylation of internal alkynes.
Scheme 33: Photoredox nickel-catalyzed hydroalkylation of activated alkynes with C(sp3)−H bonds.
Scheme 34: Allylation of unactivated C(sp3)−H bonds with allylic chlorides.
Scheme 35: Photochemical nickel-catalyzed α-amino C(sp3)–H allylation of secondary amides with trifluoromethyl...
Scheme 36: Photoredox δ C(sp3)‒H allylation of secondary amides with trifluoromethylated alkenes.
Scheme 37: Photoredox nickel-catalyzed acylation of α-amino C(sp3)‒H bonds of N-arylamines.
Figure 16: Proposed mechanism for the photoredox nickel-catalyzed acylation of α-amino C(sp3)–H bonds of N-ary...
Scheme 38: Photocatalytic α‑acylation of ethers with acid chlorides.
Figure 17: Proposed mechanism for the photocatalytic α‑acylation of ethers with acid chlorides.
Scheme 39: Photoredox and nickel-catalyzed C(sp3)‒H esterification with chloroformates.
Scheme 40: Photoredox nickel-catalyzed dehydrogenative coupling of benzylic and aldehydic C–H bonds.
Figure 18: Proposed reaction pathway for the photoredox nickel-catalyzed dehydrogenative coupling of benzylic ...
Scheme 41: Photoredox nickel-catalyzed enantioselective acylation of α-amino C(sp3)–H bonds with carboxylic ac...
Scheme 42: Nickel-catalyzed C(sp3)‒H acylation with N-acylsuccinimides.
Figure 19: Proposed mechanism for the nickel-catalyzed C(sp3)–H acylation with N-acylsuccinimides.
Scheme 43: Nickel-catalyzed benzylic C–H functionalization with acid chlorides 45.
Scheme 44: Photoredox nickel-catalyzed benzylic C–H acylation with N-acylsuccinimides 84.
Scheme 45: Photoredox nickel-catalyzed acylation of indoles 86 with α-oxoacids 87.
Scheme 46: Nickel-catalyzed aldehyde C–H functionalization.
Figure 20: Proposed catalytic cycle for the photoredox nickel-catalyzed aldehyde C–H functionalization.
Scheme 47: Photoredox carboxylation of methylbenzenes with CO2.
Figure 21: Proposed mechanism for the photoredox carboxylation of methylbenzenes with CO2.
Scheme 48: Decatungstate photo-HAT and nickel catalysis enabled alkene difunctionalization.
Figure 22: Proposed catalytic cycle for the decatungstate photo-HAT and nickel catalysis enabled alkene difunc...
Scheme 49: Diaryl ketone HAT catalysis and nickel catalysis enabled dicarbofunctionalization of alkenes.
Figure 23: Proposed catalytic mechanism for the diaryl ketone HAT catalysis and nickel catalysis enabled dicar...
Scheme 50: Overview of photoredox nickel-catalyzed C–H functionalizations.
On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets
- Renato L. Carvalho,
- Amanda S. de Miranda,
- Mateus P. Nunes,
- Roberto S. Gomes,
- Guilherme A. M. Jardim and
- Eufrânio N. da Silva Júnior
Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126
- -component reaction in which a cobalt-Cp*-catalyzed C–H bond addition afforded complex scaffolds in good yields (Scheme 37B and C) [193]. The authors explained the stereoselectivity by means of a mechanism involving a hydride migration suffering influence of steric effects related not only to the catalyst
- commercially available anticancer drug [192]). They achieved the C–H methylation by following two methods (method A or method B, Scheme 36A) and obtained the methylated analogues 107–119 in moderate to very high yields (Scheme 36B and C). Ellman and co-workers described a powerful and interesting three
Graphical Abstract
Scheme 1: Schematic overview of transition metals studied in C–H activation processes.
Scheme 2: (A) Known biological activities related to benzimidazole-based compounds; (B and C) an example of a...
Scheme 3: (A) Known biological activities related to quinoline-based compounds; (B and C) an example of a sca...
Scheme 4: (A) Known biological activities related to sulfur-containing compounds; (B and C) an example of a s...
Scheme 5: (A) Known biological activities related to aminoindane derivatives; (B and C) an example of a scand...
Scheme 6: (A) Known biological activities related to norbornane derivatives; (B and C) an example of a scandi...
Scheme 7: (A) Known biological activities related to aniline derivatives; (B and C) an example of a titanium-...
Scheme 8: (A) Known biological activities related to cyclohexylamine derivatives; (B) an example of an intram...
Scheme 9: (A) Known biologically active benzophenone derivatives; (B and C) photocatalytic oxidation of benzy...
Scheme 10: (A) Known bioactive fluorine-containing compounds; (B and C) vanadium-mediated C(sp3)–H fluorinatio...
Scheme 11: (A) Known biologically active Lythraceae alkaloids; (B) synthesis of (±)-decinine (30).
Scheme 12: (A) Synthesis of (R)- and (S)-boehmeriasin (31); (B) synthesis of phenanthroindolizidines by vanadi...
Scheme 13: (A) Known bioactive BINOL derivatives; (B and C) vanadium-mediated oxidative coupling of 2-naphthol...
Scheme 14: (A) Known antiplasmodial imidazopyridazines; (B) practical synthesis of 41.
Scheme 15: (A) Gold-catalyzed drug-release mechanism using 2-alkynylbenzamides; (B and C) chromium-mediated al...
Scheme 16: (A) Examples of anti-inflammatory benzaldehyde derivatives; (B and C) chromium-mediated difunctiona...
Scheme 17: (A and B) Manganese-catalyzed chemoselective intramolecular C(sp3)–H amination; (C) late-stage modi...
Scheme 18: (A and B) Manganese-catalyzed C(sp3)–H amination; (C) late-stage modification of a leelamine deriva...
Scheme 19: (A) Known bioactive compounds containing substituted N-heterocycles; (B and C) manganese-catalyzed ...
Scheme 20: (A) Known indoles that present GPR40 full agonist activity; (B and C) manganese-catalyzed C–H alkyl...
Scheme 21: (A) Examples of known biaryl-containing drugs; (B and C) manganese-catalyzed C–H arylation through ...
Scheme 22: (A) Known zidovudine derivatives with potent anti-HIV properties; (B and C) manganese-catalyzed C–H...
Scheme 23: (A and B) Manganese-catalyzed C–H organic photo-electrosynthesis; (C) late-stage modification.
Scheme 24: (A) Example of a known antibacterial silylated dendrimer; (B and C) manganese-catalyzed C–H silylat...
Scheme 25: (A and B) Fe-based small molecule catalyst applied for selective aliphatic C–H oxidations; (C) late...
Scheme 26: (A) Examples of naturally occurring gracilioethers; (B) the first total synthesis of gracilioether ...
Scheme 27: (A and B) Selective aliphatic C–H oxidation of amino acids; (C) late-stage modification of proline-...
Scheme 28: (A) Examples of Illicium sesquiterpenes; (B) first chemical synthesis of (+)-pseudoanisatin (80) in...
Scheme 29: (A and B) Fe-catalyzed deuteration; (C) late-stage modification of pharmaceuticals.
Scheme 30: (A and B) Biomimetic Fe-catalyzed aerobic oxidation of methylarenes to benzaldehydes (PMHS, polymet...
Scheme 31: (A) Known tetrahydroquinolines with potential biological activities; (B and C) redox-selective Fe c...
Scheme 32: (A) Known drugs containing a benzofuran unit; (B and C) Fe/Cu-catalyzed tandem O-arylation to acces...
Scheme 33: (A) Known azaindolines that act as M4 muscarinic acetylcholine receptor agonists; (B and C) intramo...
Scheme 34: (A) Known indolinones with anticholinesterase activity; (B and C) oxidative C(sp3)–H cross coupling...
Scheme 35: (A and B) Cobalt-catalyzed C–H alkenylation of C-3-peptide-containing indoles; (C) derivatization b...
Scheme 36: (A) Cobalt-Cp*-catalyzed C–H methylation of known drugs; (B and C) scope of the o-methylated deriva...
Scheme 37: (A) Known lasalocid A analogues; (B and C) three-component cobalt-catalyzed C–H bond addition; (D) ...
Scheme 38: (A and B) Cobalt-catalyzed C(sp2)–H amidation of thiostrepton.
Scheme 39: (A) Known 4H-benzo[d][1,3]oxazin-4-one derivatives with hypolipidemic activity; (B and C) cobalt-ca...
Scheme 40: (A and B) Cobalt-catalyzed C–H arylation of pyrrole derivatives; (C) application for the synthesis ...
Scheme 41: (A) Known 2-phenoxypyridine derivatives with potent herbicidal activity; (B and C) cobalt-catalyzed...
Scheme 42: (A) Natural cinnamic acid derivatives; (B and C) cobalt-catalyzed C–H carboxylation of terminal alk...
Scheme 43: (A and B) Cobalt-catalyzed C–H borylation; (C) application to the synthesis of flurbiprofen.
Scheme 44: (A) Benzothiazoles known to present anticonvulsant activities; (B and C) cobalt/ruthenium-catalyzed...
Scheme 45: (A and B) Cobalt-catalyzed oxygenation of methylene groups towards ketone synthesis; (C) synthesis ...
Scheme 46: (A) Known anticancer tetralone derivatives; (B and C) cobalt-catalyzed C–H difluoroalkylation of ar...
Scheme 47: (A and B) Cobalt-catalyzed C–H thiolation; (C) application in the synthesis of quetiapine (153).
Scheme 48: (A) Known benzoxazole derivatives with anticancer, antifungal, and antibacterial activities; (B and...
Scheme 49: (A and B) Cobalt-catalyzed C–H carbonylation of naphthylamides; (C) BET inhibitors 158 and 159 tota...
Scheme 50: (A) Known bioactive pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives; (B and C) cobalt-catalyzed C–H ...
Scheme 51: (A) Known antibacterial cyclic sulfonamides; (B and C) cobalt-catalyzed C–H amination of propargyli...
Scheme 52: (A and B) Cobalt-catalyzed intramolecular 1,5-C(sp3)–H amination; (C) late-stage functionalization ...
Scheme 53: (A and B) Cobalt-catalyzed C–H/C–H cross-coupling between benzamides and oximes; (C) late-state syn...
Scheme 54: (A) Known anticancer natural isoquinoline derivatives; (B and C) cobalt-catalyzed C(sp2)–H annulati...
Scheme 55: (A) Enantioselective intramolecular nickel-catalyzed C–H activation; (B) bioactive obtained motifs;...
Scheme 56: (A and B) Nickel-catalyzed α-C(sp3)–H arylation of ketones; (C) application of the method using kno...
Scheme 57: (A and B) Nickel-catalyzed C(sp3)–H acylation of pyrrolidine derivatives; (C) exploring the use of ...
Scheme 58: (A) Nickel-catalyzed C(sp3)–H arylation of dioxolane; (B) library of products obtained from biologi...
Scheme 59: (A) Intramolecular enantioselective nickel-catalyzed C–H cycloalkylation; (B) product examples, inc...
Scheme 60: (A and B) Nickel-catalyzed C–H deoxy-arylation of azole derivatives; (C) late-stage functionalizati...
Scheme 61: (A and B) Nickel-catalyzed decarbonylative C–H arylation of azole derivatives; (C) application of t...
Scheme 62: (A and B) Another important example of nickel-catalyzed C–H arylation of azole derivatives; (C) app...
Scheme 63: (A and B) Another notable example of a nickel-catalyzed C–H arylation of azole derivatives; (C) lat...
Scheme 64: (A and B) Nickel-based metalorganic framework (MOF-74-Ni)-catalyzed C–H arylation of azole derivati...
Scheme 65: (A) Known commercially available benzothiophene-based drugs; (B and C) nickel-catalyzed C–H arylati...
Scheme 66: (A) Known natural tetrahydrofuran-containing substances; (B and C) nickel-catalyzed photoredox C(sp3...
Scheme 67: (A and B) Another notable example of a nickel-catalyzed photoredox C(sp3)–H alkylation/arylation; (...
Scheme 68: (A) Electrochemical/nickel-catalyzed C–H alkoxylation; (B) achieved scope, including three using na...
Scheme 69: (A) Enantioselective photoredox/nickel catalyzed C(sp3)–H arylation; (B) achieved scope, including ...
Scheme 70: (A) Known commercially available trifluoromethylated drugs; (B and C) nickel-catalyzed C–H trifluor...
Scheme 71: (A and B) Stereoselective nickel-catalyzed C–H difluoroalkylation; (C) late-stage functionalization...
Scheme 72: (A) Cu-mediated ortho-amination of oxalamides; (B) achieved scope, including derivatives obtained f...
Scheme 73: (A) Electro-oxidative copper-mediated amination of 8-aminoquinoline-derived amides; (B) achieved sc...
Scheme 74: (A and B) Cu(I)-mediated C–H amination with oximes; (C) derivatization using telmisartan (241) as s...
Scheme 75: (A and B) Cu-mediated amination of aryl amides using ammonia; (C) late-stage modification of proben...
Scheme 76: (A and B) Synthesis of purine nucleoside analogues using copper-mediated C(sp2)–H activation.
Scheme 77: (A) Copper-mediated annulation of acrylamide; (B) achieved scope, including the synthesis of the co...
Scheme 78: (A) Known bioactive compounds containing a naphthyl aryl ether motif; (B and C) copper-mediated eth...
Scheme 79: (A and B) Cu-mediated alkylation of N-oxide-heteroarenes; (C) late-stage modification.
Scheme 80: (A) Cu-mediated cross-dehydrogenative coupling of polyfluoroarenes and alkanes; (B) scope from know...
Scheme 81: (A) Known anticancer acrylonitrile compounds; (B and C) Copper-mediated cyanation of unactivated al...
Scheme 82: (A) Cu-mediated radiofluorination of 8-aminoquinoline-derived aryl amides; (B) achieved scope, incl...
Scheme 83: (A) Examples of natural β-carbolines; (B and C) an example of a zinc-catalyzed C–H functionalizatio...
Scheme 84: (A) Examples of anticancer α-aminophosphonic acid derivatives; (B and C) an example of a zinc-catal...
Icilio Guareschi and his amazing “1897 reaction”
- Gian Cesare Tron,
- Alberto Minassi,
- Giovanni Sorba,
- Mara Fausone and
- Giovanni Appendino
Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93
- industrialized total synthesis of a nontrivial natural product. The original experimental protocol was recently improved by replacing the inorganic base (KOH, NaOH) with the amidine base diazobicycloundecane (DBU) as well as ethanol with n-propanol [49]. The type-III Guareschi reaction is a three-component
- reaction reported in 1898 [50]. It involves the reaction of a β-dicarbonyl (ester or diketone) with a primary amine or ammonia and a cyanoacetic ester. The mechanism of this condensation closely resembles the three-component version of the Hantzsch pyridine synthesis and generates 6-hydroxypyridones. Also
Graphical Abstract
Figure 1: Icilio Guareschi (1847–1918). (Source: Annali della Reale Accademia di Agricoltura di Torino 1919, ...
Scheme 1: Vitamin B6 (pyridoxine, 1), gabapentin (2), and thymol (3).
Figure 2: Baliatico (Nursing) by Francesco Scaramuzza (275 cm × 214 cm, Parma, Complesso Museale della Pilott...
Figure 3: Schiff’s fictitious report on the foundation of the Gazzetta Chimica Italiana (Image reproduced fro...
Scheme 2: Reaction of thymol (3) with chloroform under the basic conditions of the Guareschi–Lustgarten react...
Figure 4: The chemistry building of Turin University in a historical picture. Note, that one of the “mysterio...
Scheme 3: Triacetonamine (6) and the related compounds phorone (7), α-eucaine (8), and tropinone (9).
Scheme 4: Taxonomy of the Guareschi pyridone syntheses.
Scheme 5: The catalytic cycle of the “1897 reaction”.
Scheme 6: Resonance forms of the radical 10.
Figure 5: The wet chamber used by Guareschi to restore parchments (Gorrini, G. L'incendio della R. Biblioteca...
Figure 6: The Guareschi mask. (Servizio Chimico Militare. L'opera di Icilio Guareschi precursore della masche...
Figure 7: Guareschi’s bust at the Dipartimento di Scienza e Tecnologia del Farmaco of Turin University. Permi...
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
Graphical Abstract
Figure 1: Representative shares of the global F&F market (2018) segmented on their applications [1].
Figure 2: General structure of an international fragrance company [2].
Figure 3: The Michael Edwards fragrance wheel.
Figure 4: Examples of oriental (1–3), woody (4–7), fresh (8–10), and floral (11 and 12) notes.
Figure 5: A basic depiction of batch vs flow.
Scheme 1: Examples of reactions for which flow processing outperforms batch.
Scheme 2: Some industrially important aldol-based transformations.
Scheme 3: Biphasic continuous aldol reactions of acetone and various aldehydes.
Scheme 4: Aldol synthesis of 43 in flow using LiHMDS as the base.
Scheme 5: A semi-continuous synthesis of doravirine (49) involving a key aldol reaction.
Scheme 6: Enantioselective aldol reaction using 5-(pyrrolidin-2-yl)tetrazole (51) as catalyst in a microreact...
Scheme 7: Gröger's example of asymmetric aldol reaction in aqueous media.
Figure 6: Immobilised reagent column reactor types.
Scheme 8: Photoinduced thiol–ene coupling preparation of silica-supported 5-(pyrrolidin-2-yl)tetrazole 63 and...
Scheme 9: Continuous-flow approach for enantioselective aldol reactions using the supported catalyst 67.
Scheme 10: Ötvös’ employment of a solid-supported peptide aldol catalyst in flow.
Scheme 11: The use of proline tetrazole packed in a column for aldol reaction between cyclohexanone (65) and 2...
Scheme 12: Schematic diagram of an aminosilane-grafted Si-Zr-Ti/PAI-HF reactor for continuous-flow aldol and n...
Scheme 13: Continuous-flow condensation for the synthesis of the intermediate 76 to nabumetone (77) and Microi...
Scheme 14: Synthesis of ψ-Ionone (80) in continuous-flow via aldol condensation between citral (79) and aceton...
Scheme 15: Synthesis of β-methyl-ionones (83) from citral (79) in flow. The steps are separately described, an...
Scheme 16: Continuous-flow synthesis of 85 from 84 described by Gavriilidis et al.
Scheme 17: Continuous-flow scCO2 apparatus for the synthesis of 2-methylpentanal (87) and the self-condensed u...
Scheme 18: Chen’s two-step flow synthesis of coumarin (90).
Scheme 19: Pechmann condensation for the synthesis of 7-hydroxyxcoumarin (93) in flow. The setup extended to c...
Scheme 20: Synthesis of the dihydrojasmonate 35 exploiting nitro derivative proposed by Ballini et al.
Scheme 21: Silica-supported amines as heterogeneous catalyst for nitroaldol condensation in flow.
Scheme 22: Flow apparatus for the nitroaldol condensation of p-hydroxybenzaldehyde (102) to nitrostyrene 103 a...
Scheme 23: Nitroaldol reaction of 64 to 105 employing a quaternary ammonium functionalised PANF.
Scheme 24: Enantioselective nitroaldol condensation for the synthesis of 108 under flow conditions.
Scheme 25: Enatioselective synthesis of 1,2-aminoalcohol 110 via a copper-catalysed nitroaldol condensation.
Scheme 26: Examples of Knoevenagel condensations applied for fragrance components.
Scheme 27: Flow apparatus for Knoevenagel condensation described in 1989 by Venturello et al.
Scheme 28: Knoevenagel reaction using a coated multichannel membrane microreactor.
Scheme 29: Continuous-flow apparatus for Knoevenagel condensation employing sugar cane bagasse as support deve...
Scheme 30: Knoevenagel reaction for the synthesis of 131–135 in flow using an amine-functionalised silica gel. ...
Scheme 31: Continuous-flow synthesis of compound 137, a key intermediate for the synthesis of pregabalin (138)...
Scheme 32: Continuous solvent-free apparatus applied for the synthesis of compounds 140–143 using a TSE. Throu...
Scheme 33: Lewis et al. developed a spinning disc reactor for Darzens condensation of 144 and a ketone to furn...
Scheme 34: Some key industrial applications of conjugate additions in the F&F industry.
Scheme 35: Continuous-flow synthesis of 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide (156) via double conjugat...
Scheme 36: Continuous-flow system for Michael addition using CsF on alumina as the catalyst.
Scheme 37: Calcium chloride-catalysed asymmetric Michael addition using an immobilised chiral ligand.
Scheme 38: Continuous multistep synthesis for the preparation of (R)-rolipram (173). Si-NH2: primary amine-fun...
Scheme 39: Continuous-flow Michael addition using ion exchange resin Amberlyst® A26.
Scheme 40: Preparation of the heterogeneous catalyst 181 developed by Paixão et al. exploiting Ugi multicompon...
Scheme 41: Continuous-flow system developed by the Paixão’s group for the preparation of Michael asymmetric ad...
Scheme 42: Continuous-flow synthesis of nitroaldols catalysed by supported catalyst 184 developed by Wennemers...
Scheme 43: Heterogenous polystyrene-supported catalysts developed by Pericàs and co-workers.
Scheme 44: PANF-supported pyrrolidine catalyst for the conjugate addition of cyclohexanone (65) and trans-β-ni...
Scheme 45: Synthesis of (−)-paroxetine precursor 195 developed by Ötvös, Pericàs, and Kappe.
Scheme 46: Continuous-flow approach for the 5-step synthesis of (−)-oseltamivir (201) as devised by Hayashi an...
Scheme 47: Continuous-flow enzyme-catalysed Michael addition.
Scheme 48: Continuous-flow copper-catalysed 1,4 conjugate addition of Grignard reagents to enones. Reprinted w...
Scheme 49: A collection of commonly encountered hydrogenation reactions.
Figure 7: The ThalesNano H-Cube® continuous-flow hydrogenator.
Scheme 50: Chemoselective reduction of an α,β-unsaturated ketone using the H-Cube® reactor.
Scheme 51: Incorporation of Lindlar’s catalyst into the H-Cube® reactor for the reduction of an alkyne.
Scheme 52: Continuous-flow semi-hydrogenation of alkyne 208 to 209 using SACs with H-Cube® system.
Figure 8: The standard setups for tube-in-tube gas–liquid reactor units.
Scheme 53: Homogeneous hydrogenation of olefins using a tube-in-tube reactor setup.
Scheme 54: Recyclable heterogeneous flow hydrogenation system.
Scheme 55: Leadbeater’s reverse tube-in-tube hydrogenation system for olefin reductions.
Scheme 56: a) Hydrogenation using a Pd-immobilised microchannel reactor (MCR) and b) a representation of the i...
Scheme 57: Hydrogenation of alkyne 238 exploiting segmented flow in a Pd-immobilised capillary reactor.
Scheme 58: Continuous hydrogenation system for the preparation of cyrene (241) from (−)-levoglucosenone (240).
Scheme 59: Continuous hydrogenation system based on CSMs developed by Hornung et al.
Scheme 60: Chemoselective reduction of carbonyls (ketones over aldehydes) in flow.
Scheme 61: Continuous system for the semi-hydrogenation of 256 and 258, developed by Galarneau et al.
Scheme 62: Continuous synthesis of biodiesel fuel 261 from lignin-derived furfural acetone (260).
Scheme 63: Continuous synthesis of γ-valerolacetone (263) via CTH developed by Pineda et al.
Scheme 64: Continuous hydrogenation of lignin-derived biomass (products 265, 266, and 267) using a sustainable...
Scheme 65: Ru/C or Rh/C-catalysed hydrogenation of arene in flow as developed by Sajiki et al.
Scheme 66: Polysilane-immobilized Rh–Pt-catalysed hydrogenation of arenes in flow by Kobayashi et al.
Scheme 67: High-pressure in-line mixing of H2 for the asymmetric reduction of 278 at pilot scale with a 73 L p...
Figure 9: Picture of the PFR employed at Eli Lilly & Co. for the continuous hydrogenation of 278 [287]. Reprinted ...
Scheme 68: Continuous-flow asymmetric hydrogenation using Oppolzer's sultam 280 as chiral auxiliary.
Scheme 69: Some examples of industrially important oxidation reactions in the F&F industry. CFL: compact fluor...
Scheme 70: Gold-catalysed heterogeneous oxidation of alcohols in flow.
Scheme 71: Uozumi’s ARP-Pt flow oxidation protocol.
Scheme 72: High-throughput screening of aldehyde oxidation in flow using an in-line GC.
Scheme 73: Permanganate-mediated Nef oxidation of nitroalkanes in flow with the use of in-line sonication to p...
Scheme 74: Continuous-flow aerobic anti-Markovnikov Wacker oxidation.
Scheme 75: Continuous-flow oxidation of 2-benzylpyridine (312) using air as the oxidant.
Scheme 76: Continuous-flow photo-oxygenation of monoterpenes.
Scheme 77: A tubular reactor design for flow photo-oxygenation.
Scheme 78: Glucose oxidase (GOx)-mediated continuous oxidation of glucose using compressed air and the FFMR re...
Scheme 79: Schematic continuous-flow sodium hypochlorite/TEMPO oxidation of alcohols.
Scheme 80: Oxidation using immobilised TEMPO (344) was developed by McQuade et al.
Scheme 81: General protocol for the bleach/catalytic TBAB oxidation of aldehydes and alcohols.
Scheme 82: Continuous-flow PTC-assisted oxidation using hydrogen peroxide. The process was easily scaled up by...
Scheme 83: Continuous-flow epoxidation of cyclohexene (348) and in situ preparation of m-CPBA.
Scheme 84: Continuous-flow epoxidation using DMDO as oxidant.
Scheme 85: Mukayama aerobic epoxidation optimised in flow mode by the Favre-Réguillon group.
Scheme 86: Continuous-flow asymmetric epoxidation of derivatives of 359 exploiting a biomimetic iron catalyst.
Scheme 87: Continuous-flow enzymatic epoxidation of alkenes developed by Watts et al.
Scheme 88: Engineered multichannel microreactor for continuous-flow ozonolysis of 366.
Scheme 89: Continuous-flow synthesis of the vitamin D precursor 368 using multichannel microreactors. MFC: mas...
Scheme 90: Continuous ozonolysis setup used by Kappe et al. for the synthesis of various substrates employing ...
Scheme 91: Continuous-flow apparatus for ozonolysis as developed by Ley et al.
Scheme 92: Continuous-flow ozonolysis for synthesis of vanillin (2) using a film-shear flow reactor.
Scheme 93: Examples of preparative methods for ajoene (386) and allicin (388).
Scheme 94: Continuous-flow oxidation of thioanisole (389) using styrene-based polymer-supported peroxytungstat...
Scheme 95: Continuous oxidation of thiosulfinates using Oxone®-packed reactor.
Scheme 96: Continuous-flow electrochemical oxidation of thioethers.
Scheme 97: Continuous-flow oxidation of 400 to cinnamophenone (235).
Scheme 98: Continuous-flow synthesis of dehydrated material 401 via oxidation of methyl dihydrojasmonate (33).
Scheme 99: Some industrially important transformations involving Grignard reagents.
Scheme 100: Grachev et al. apparatus for continuous preparation of Grignard reagents.
Scheme 101: Example of fluidized Mg bed reactor with NMR spectrometer as on-line monitoring system.
Scheme 102: Continuous-flow synthesis of Grignard reagents and subsequent quenching reaction.
Figure 10: Membrane-based, liquid–liquid separator with integrated pressure control [52]. Adapted with permission ...
Scheme 103: Continuous-flow synthesis of 458, an intermediate to fluconazole (459).
Scheme 104: Continuous-flow synthesis of ketones starting from benzoyl chlorides.
Scheme 105: A Grignard alkylation combining CSTR and PFR technologies with in-line infrared reaction monitoring....
Scheme 106: Continuous-flow preparation of 469 from Grignard addition of methylmagnesium bromide.
Scheme 107: Continuous-flow synthesis of Grignard reagents 471.
Scheme 108: Preparation of the Grignard reagent 471 using CSTR and the continuous process for synthesis of the ...
Scheme 109: Continuous process for carboxylation of Grignard reagents in flow using tube-in-tube technology.
Scheme 110: Continuous synthesis of propargylic alcohols via ethynyl-Grignard reagent.
Scheme 111: Silica-supported catalysed enantioselective arylation of aldehydes using Grignard reagents in flow ...
Scheme 112: Acid-catalysed rearrangement of citral and dehydrolinalool derivatives.
Scheme 113: Continuous stilbene isomerisation with continuous recycling of photoredox catalyst.
Scheme 114: Continuous-flow synthesis of compound 494 as developed by Ley et al.
Scheme 115: Selected industrial applications of DA reaction.
Scheme 116: Multistep flow synthesis of the spirocyclic structure 505 via employing DA cycloaddition.
Scheme 117: Continuous-flow DA reaction developed in a plater flow reactor for the preparation of the adduct 508...
Scheme 118: Continuous-flow DA reaction using a silica-supported imidazolidinone organocatalyst.
Scheme 119: Batch vs flow for the DA reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane (513) with acrylon...
Scheme 120: Continuous-flow DA reaction between 510 and 515 using a shell-core droplet system.
Scheme 121: Continuous-flow synthesis of bicyclic systems from benzyne precursors.
Scheme 122: Continuous-flow synthesis of bicyclic scaffolds 527 and 528 for further development of potential ph...
Scheme 123: Continuous-flow inverse-electron hetero-DA reaction to pyridine derivatives such as 531.
Scheme 124: Comparison between batch and flow for the synthesis of pyrimidinones 532–536 via retro-DA reaction ...
Scheme 125: Continuous-flow coupled with ultrasonic system for preparation of ʟ-ascorbic acid derivatives 539 d...
Scheme 126: Two-step continuous-flow synthesis of triazole 543.
Scheme 127: Continuous-flow preparation of triazoles via CuAAC employing 546-based heterogeneous catalyst.
Scheme 128: Continuous-flow synthesis of compounds 558 through A3-coupling and 560 via AgAAC both employing the...
Scheme 129: Continuous-flow photoinduced [2 + 2] cycloaddition for the preparation of bicyclic derivatives of 5...
Scheme 130: Continuous-flow [2 + 2] and [5 + 2] cycloaddition on large scale employing a flow reactor developed...
Scheme 131: Continuous-flow preparation of the tricyclic structures 573 and 574 starting from pyrrole 570 via [...
Scheme 132: Continuous-flow [2 + 2] photocyclization of cinnamates.
Scheme 133: Continuous-flow preparation of cyclobutane 580 on a 5-plates photoreactor.
Scheme 134: Continuous-flow [2 + 2] photocycloaddition under white LED lamp using heterogeneous PCN as photocat...
Figure 11: Picture of the parallel tube flow reactor (PTFR) "The Firefly" developed by Booker-Milburn et al. a...
Scheme 135: Continuous-flow acid-catalysed [2 + 2] cycloaddition between silyl enol ethers and acrylic esters.
Scheme 136: Continuous synthesis of lactam 602 using glass column reactors.
Scheme 137: In situ generation of ketenes for the Staudinger lactam synthesis developed by Ley and Hafner.
Scheme 138: Application of [2 + 2 + 2] cycloadditions in flow employed by Ley et al.
Scheme 139: Examples of FC reactions applied in F&F industry.
Scheme 140: Continuous-flow synthesis of ibuprofen developed by McQuade et al.
Scheme 141: The FC acylation step of Jamison’s three-step ibuprofen synthesis.
Scheme 142: Synthesis of naphthalene derivative 629 via FC acylation in microreactors.
Scheme 143: Flow system for rapid screening of catalysts and reaction conditions developed by Weber et al.
Scheme 144: Continuous-flow system developed by Buorne, Muller et al. for DSD optimisation of the FC acylation ...
Scheme 145: Continuous-flow FC acylation of alkynes to yield β-chlorovinyl ketones such as 638.
Scheme 146: Continuous-flow synthesis of tonalide (619) developed by Wang et al.
Scheme 147: Continuous-flow preparation of acylated arene such as 290 employing Zr4+-β-zeolite developed by Kob...
Scheme 148: Flow system applied on an Aza-FC reaction catalysed by the thiourea catalyst 648.
Scheme 149: Continuous hydroformylation in scCO2.
Scheme 150: Two-step flow synthesis of aldehyde 655 through a sequential Heck reaction and subsequent hydroform...
Scheme 151: Single-droplet (above) and continuous (below) flow reactors developed by Abolhasani et al. for the ...
Scheme 152: Continuous hydroformylation of 1-dodecene (655) using a PFR-CSTR system developed by Sundmacher et ...
Scheme 153: Continuous-flow synthesis of the aldehyde 660 developed by Eli Lilly & Co. [32]. Adapted with permissio...
Scheme 154: Continuous asymmetric hydroformylation employing heterogenous catalst supported on carbon-based sup...
Scheme 155: Examples of acetylation in F&F industry: synthesis of bornyl (S,R,S-664) and isobornyl (S,S,S-664) ...
Scheme 156: Continuous-flow preparation of bornyl acetate (S,R,S-664) employing the oscillating flow reactor.
Scheme 157: Continuous-flow synthesis of geranyl acetate (666) from acetylation of geraniol (343) developed by ...
Scheme 158: 12-Ttungstosilicic acid-supported silica monolith-catalysed acetylation in flow.
Scheme 159: Continuous-flow preparation of cyclopentenone 676.
Scheme 160: Two-stage synthesis of coumarin (90) via acetylation of salicylaldehyde (88).
Scheme 161: Intensification process for acetylation of 5-methoxytryptamine (677) to melatonin (678) developed b...
Scheme 162: Examples of macrocyclic musky odorants both natural (679–681) and synthetic (682 and 683).
Scheme 163: Flow setup combined with microwave for the synthesis of macrocycle 686 via RCM.
Scheme 164: Continuous synthesis of 2,5-dihydro-1H-pyrroles via ring-closing metathesis.
Scheme 165: Continuous-flow metathesis of 485 developed by Leadbeater et al.
Figure 12: Comparison between RCM performed using different routes for the preparation of 696. On the left the...
Scheme 166: Continuous-flow RCM of 697 employed the solid-supported catalyst 698 developed by Grela, Kirschning...
Scheme 167: Continuous-flow RORCM of cyclooctene employing the silica-absorbed catalyst 700.
Scheme 168: Continuous-flow self-metathesis of methyl oleate (703) employing SILP catalyst 704.
Scheme 169: Flow apparatus for the RCM of 697 using a nanofiltration membrane for the recovery and reuse of the...
Scheme 170: Comparison of loadings between RCMs performed with different routes for the synthesis of 709.
Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects
- Shivani Gulati,
- Stephy Elza John and
- Nagula Shankaraiah
Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71
- ; 4, Figure 1) [36][37]. The relevance of acridine in drug discovery galvanized Singh and co-workers [38] to develop a water-promoted three-component reaction involving aldehydes 5, cyclic 1,3-diketone 6 and ammonium acetate powered by microwave irradiation resulting in 4-arylacridinediones 7 in
- with N,O-acetyl intermediate E, this may lead to the formation of a very hindered intermediate C via SN2 inversion of B and thus favors the involvement of pathway A rather than pathway B. Simultaneously, Li and co-workers [46] reported a three-component reaction for the synthesis of benzo[f]azulen-1
- marketed drugs structured around indole implying its pharmacological significance such as oxypertine (27), ateviridine (28) [47] and spirooxindole-based potent cytotoxic agents 29, 30 and 31 [48]. In 2017, Lin and co-workers [49] designed a TFA-catalyzed three-component reaction for the regioselective
Graphical Abstract
Figure 1: Marketed drugs with acridine moiety.
Scheme 1: Synthesis of 4-arylacridinediones.
Scheme 2: Proposed mechanism for acridinedione synthesis.
Scheme 3: Synthesis of tetrahydrodibenzoacridinones.
Scheme 4: Synthesis of naphthoacridines.
Scheme 5: Plausible mechanism for naphthoacridines.
Figure 2: Benzoazepines based potent molecules.
Scheme 6: Synthesis of azepinone.
Scheme 7: Proposed mechanism for azepinone formation.
Scheme 8: Synthesis of benzoazulenen-1-one derivatives.
Scheme 9: Proposed mechanism for benzoazulene-1-one synthesis.
Figure 3: Indole-containing pharmacologically active molecules.
Scheme 10: Synthesis of functionalized indoles.
Scheme 11: Plausible mechanism for the synthesis of functionalized indoles.
Scheme 12: Synthesis of spirooxindoles.
Scheme 13: Synthesis of substituted spirooxindoles.
Scheme 14: Plausible mechanism for the synthesis of substituted spirooxindoles.
Scheme 15: Synthesis of pyrrolidinyl spirooxindoles.
Scheme 16: Proposed mechanism for pyrrolidinyl spirooxindoles.
Figure 4: Pyran-containing biologically active molecules.
Scheme 17: Synthesis of functionalized benzopyrans.
Scheme 18: Plausible mechanism for synthesis of benzopyran.
Scheme 19: Synthesis of indoline-spiro-fused pyran derivatives.
Scheme 20: Proposed mechanism for indoline-spiro-fused pyran.
Scheme 21: Synthesis of substituted naphthopyrans.
Figure 5: Marketed drugs with pyrrole ring.
Scheme 22: Synthesis of tetra-substituted pyrroles.
Scheme 23: Mechanism for silica-supported PPA-SiO2-catalyzed pyrrole synthesis.
Scheme 24: Synthesis of pyrrolo[1,10]-phenanthrolines.
Scheme 25: Proposed mechanism for pyrrolo[1,10]-phenanthrolines.
Figure 6: Marketed drugs and molecules containing pyrimidine and pyrimidinones skeletons.
Scheme 26: MWA-MCR pyrimidinone synthesis.
Scheme 27: Two proposed mechanisms for pyrimidinone synthesis.
Scheme 28: MWA multicomponent synthesis of dihydropyrimidinones.
Scheme 29: Proposed mechanism for dihydropyrimidinones.
Figure 7: Biologically active fused pyrimidines.
Scheme 30: MWA- MCR for the synthesis of pyrrolo[2,3-d]pyrimidines.
Scheme 31: Proposed mechanism for pyrrolo[2,3-d]pyrimidines.
Scheme 32: Synthesis of substituted pyrrolo[2,3-d]pyrimidine-2,4-diones.
Scheme 33: Probable pathway for pyrrolo[2,3-d]pyrimidine-2,4-diones.
Scheme 34: Synthesis of pyridopyrimidines.
Scheme 35: Plausible mechanism for the synthesis of pyridopyrimidines.
Scheme 36: Synthesis of dihydropyridopyrimidine and dihydropyrazolopyridine.
Scheme 37: Proposed mechanism for the formation of dihydropyridopyrimidine.
Scheme 38: Synthesis of thiopyrano[4,3-d]pyrimidines.
Scheme 39: Plausible mechanism for the synthesis of thiopyrano[4,3-d]pyrimidines.
Scheme 40: Synthesis of decorated imidazopyrimidines.
Scheme 41: Proposed mechanism for imidazopyrimidine synthesis.
Figure 8: Pharmacologically active molecules containing purine bases.
Scheme 42: Synthesis of aza-adenines.
Scheme 43: Synthesis of 5-aza-7-deazapurines.
Scheme 44: Proposed mechanism for deazapurines synthesis.
Figure 9: Biologically active molecules containing pyridine moiety.
Scheme 45: Synthesis of steroidal pyridines.
Scheme 46: Proposed mechanism for steroidal pyridine.
Scheme 47: Synthesis of N-alkylated 2-pyridones.
Scheme 48: Two possible mechanisms for pyridone synthesis.
Scheme 49: Synthesis of pyridone derivatives.
Scheme 50: Postulated mechanism for synthesis of pyridone.
Figure 10: Biologically active fused pyridines.
Scheme 51: Benzimidazole-imidazo[1,2-a]pyridines synthesis.
Scheme 52: Mechanism for the synthesis of benzimidazole-imidazo[1,2-a]pyridines.
Scheme 53: Synthesis of pyrazolo[3,4-b]pyridine-5-spirocycloalkanedione derivatives.
Scheme 54: Proposed mechanism for spiro-pyridines.
Scheme 55: Functionalized macrocyclane-fused pyrazolo[3,4-b]pyridine derivatives.
Scheme 56: Mechanism postulated for macrocyclane-fused pyrazolo[3,4-b]pyridine.
Scheme 57: Generation of pyrazolo[3,4-b]pyridines.
Scheme 58: Proposed mechanism for the synthesis of pyrazolo[3,4-b]pyridines.
Scheme 59: Proposed mechanism for the synthesis of azepinoindole.
Figure 11: Pharmaceutically important molecules with quinoline moiety.
Scheme 60: Povarov-mediated quinoline synthesis.
Scheme 61: Proposed mechanism for Povarov reaction.
Scheme 62: Synthesis of pyrazoloquinoline.
Scheme 63: Plausible mechanism for pyrazoloquinoline synthesis.
Figure 12: Quinazolinones as pharmacologically significant scaffolds.
Scheme 64: Four-component reaction for dihydroquinazolinone.
Scheme 65: Proposed mechanism for dihydroquinazolinones.
Scheme 66: Synthesis purine quinazolinone and PI3K-δ inhibitor.
Scheme 67: Synthesis of fused benzothiazolo/benzoimidazoloquinazolinones.
Scheme 68: Proposed mechanism for fused benzothiazolo/benzoimidazoloquinazolinones.
Scheme 69: On-water reaction for synthesis of thiazoloquinazolinone.
Scheme 70: Proposed mechanism for the thiazoloquinazolinone synthesis.
Scheme 71: β-Cyclodextrin-mediated synthesis of indoloquinazolinediones.
Scheme 72: Proposed mechanism for synthesis of indoloquinazolinediones.
Figure 13: Triazoles-containing marketted drugs and pharmacologically active molecules.
Scheme 73: Cu(I) DAPTA-catalyzed 1,2,3-triazole formation.
Scheme 74: Mechanism for Cu(I) DAPTA-catalyzed triazole formation.
Scheme 75: Synthesis of β-hydroxy-1,2,3-triazole.
Scheme 76: Proposed mechanism for synthesis of β-hydroxy-1,2,3-triazoles.
Scheme 77: Synthesis of bis-1,2,4-triazoles.
Scheme 78: Proposed mechanism for bis-1,2,4-triazoles synthesis.
Figure 14: Thiazole containing drugs.
Scheme 79: Synthesis of a substituted thiazole ring.
Scheme 80: Synthesis of pyrazolothiazoles.
Figure 15: Chromene containing drugs.
Scheme 81: Magnetic nanocatalyst-mediated aminochromene synthesis.
Scheme 82: Proposed mechanism for the synthesis of chromenes.
Synthetic reactions driven by electron-donor–acceptor (EDA) complexes
- Zhonglie Yang,
- Yutong Liu,
- Kun Cao,
- Xiaobin Zhang,
- Hezhong Jiang and
- Jiahong Li
Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67
- -bond adduct. The first light-promoted three-component reaction has been realized by a halogen-bond adduct, forming perfluoroalkylated pyrimidines 26 (Scheme 8). A variety of perfluorinated chains were assembled with methylene compounds and guanidines or amidines, giving the corresponding
- three-component reaction in the absence of light, which is of great significance for the later study of temperature-driven EDA complexes. In 2017, König and colleagues [42] discovered an EDA complex 75 formed by bromothiophene 72, aniline (73), and N,N-diisopropylethylamine (DIPEA) as organic base
- the subsequent reaction (Scheme 28). On account of a wide range of substrates and functional group compatibility, this protocol can be exploited to assemble various β-trifluoromethylated alkynes by three-component reaction without transition-metal catalysis. In 2018, Xu and colleagues [48] proposed
Graphical Abstract
Scheme 1: The electron transfer process in EDA complexes.
Scheme 2: Synthesis of benzo[b]phosphorus oxide 3 initiated by an EDA complex.
Scheme 3: Mechanism of the synthesis of quinoxaline derivative 7.
Scheme 4: Synthesis of imidazole derivative 10 initiated by an EDA complex.
Scheme 5: Synthesis of sulfamoylation product 12 initiated by an EDA complex.
Scheme 6: Mechanism of the synthesis of sulfamoylation product 12.
Scheme 7: Synthesis of indole derivative 22 initiated by an EDA complex.
Scheme 8: Synthesis of perfluoroalkylated pyrimidines 26 initiated by an EDA complex.
Scheme 9: Synthesis of phenanthridine derivative 29 initiated by an EDA complex.
Scheme 10: Synthesis of cis-tetrahydroquinoline derivative 32 initiated by an EDA complex.
Scheme 11: Mechanism of the synthesis of cis-tetrahydroquinoline derivative 32.
Scheme 12: Synthesis of phenanthridine derivative 38 initiated by an EDA complex.
Scheme 13: Synthesis of spiropyrroline derivative 40 initiated by an EDA complex.
Scheme 14: Synthesis of benzothiazole derivative 43 initiated by an EDA complex.
Scheme 15: Synthesis of perfluoroalkyl-s-triazine derivative 45 initiated by an EDA complex.
Scheme 16: Synthesis of indoline derivative 47 initiated by an EDA complex.
Scheme 17: Mechanism of the synthesis of spirocyclic indoline derivative 47.
Scheme 18: Synthesis of cyclobutane product 50 initiated by an EDA complex.
Scheme 19: Mechanism of the synthesis of spirocyclic indoline derivative 50.
Scheme 20: Synthesis of 1,3-oxazolidine compound 59 initiated by an EDA complex.
Scheme 21: Synthesis of trifluoromethylated product 61 initiated by an EDA complex.
Scheme 22: Synthesis of indole alkylation product 64 initiated by an EDA complex.
Scheme 23: Synthesis of perfluoroalkylation product 67 initiated by an EDA complex.
Scheme 24: Synthesis of hydrotrifluoromethylated product 70 initiated by an EDA complex.
Scheme 25: Synthesis of β-trifluoromethylated alkyne product 71 initiated by an EDA complex.
Scheme 26: Mechanism of the synthesis of 2-phenylthiophene derivative 74.
Scheme 27: Synthesis of allylated product 80 initiated by an EDA complex.
Scheme 28: Synthesis of trifluoromethyl-substituted alkynyl product 84 initiated by an EDA complex.
Scheme 29: Synthesis of dearomatized fluoroalkylation product 86 initiated by an EDA complex.
Scheme 30: Mechanism of the synthesis of dearomatized fluoroalkylation product 86.
Scheme 31: Synthesis of C(sp3)–H allylation product 91 initiated by an EDA complex.
Scheme 32: Synthesis of perfluoroalkylation product 93 initiated by an EDA complex.
Scheme 33: Synthesis of spirocyclic indolene derivative 95 initiated by an EDA complex.
Scheme 34: Synthesis of perfluoroalkylation product 97 initiated by an EDA complex.
Scheme 35: Synthesis of alkylated indole derivative 100 initiated by an EDA complex.
Scheme 36: Mechanism of the synthesis of alkylated indole derivative 100.
Scheme 37: Synthesis of arylated oxidized indole derivative 108 initiated by an EDA complex.
Scheme 38: Synthesis of 4-ketoaldehyde derivative 111 initiated by an EDA complex.
Scheme 39: Mechanism of the synthesis of 4-ketoaldehyde derivative 111.
Scheme 40: Synthesis of perfluoroalkylated olefin 118 initiated by an EDA complex.
Scheme 41: Synthesis of alkylation product 121 initiated by an EDA complex.
Scheme 42: Synthesis of acylation product 123 initiated by an EDA complex.
Scheme 43: Mechanism of the synthesis of acylation product 123.
Scheme 44: Synthesis of trifluoromethylation product 126 initiated by an EDA complex.
Scheme 45: Synthesis of unnatural α-amino acid 129 initiated by an EDA complex.
Scheme 46: Synthesis of thioether derivative 132 initiated by an EDA complex.
Scheme 47: Synthesis of S-aryl dithiocarbamate product 135 initiated by an EDA complex.
Scheme 48: Mechanism of the synthesis of S-aryl dithiocarbamate product 135.
Scheme 49: Synthesis of thioether product 141 initiated by an EDA complex.
Scheme 50: Mechanism of the synthesis of borate product 144.
Scheme 51: Synthesis of boronation product 148 initiated by an EDA complex.
Scheme 52: Synthesis of boration product 151 initiated by an EDA complex.
Scheme 53: Synthesis of boronic acid ester derivative 154 initiated by an EDA complex.
Scheme 54: Synthesis of β-azide product 157 initiated by an EDA complex.
Scheme 55: Decarboxylation reaction initiated by an EDA complex.
Scheme 56: Synthesis of amidated product 162 initiated by an EDA complex.
Scheme 57: Synthesis of diethyl phenylphosphonate 165 initiated by an EDA complex.
Scheme 58: Mechanism of the synthesis of diethyl phenylphosphonate derivative 165.
Scheme 59: Synthesis of (Z)-2-iodovinyl phenyl ether 168 initiated by an EDA complex.
Scheme 60: Mechanism of the synthesis of (Z)-2-iodovinyl phenyl ether derivative 168.
Scheme 61: Dehalogenation reaction initiated by an EDA complex.
Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes
- Yajing Zhang,
- Qingshan Tian,
- Guozhu Zhang and
- Dayong Zhang
Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258
- 200032, P. R. China 10.3762/bjoc.16.258 Abstract A silver-catalyzed three-component reaction involving alkynes, Selectfluor®, and diethyl phosphite was employed for the one-pot formation of C(sp2)–F and C(sp2)–P bonds to provide an efficient access to β-fluorovinylphosphonates in a highly regio- and
- subsequent fluorine atom transfer. Keywords: β-fluorovinylphosphonates; fluorine atom transfer; P-centered radical; silver catalysis; three-component reaction; Introduction As one of the most important topics in organic chemistry, the introduction of fluorine and phosphorus atoms into double bonds is an
Graphical Abstract
Scheme 1: Metal-catalyzed difunctionalization of unsaturated carbon–carbon bonds.
Scheme 2: Substrate scope for the synthesis of the β-fluorovinylphosphonates 2 using diethyl phosphite. React...
Scheme 3: Substrate scope for the synthesis of the β-fluorovinylphosphonates 3 using dimethyl phosphite. Reac...
Scheme 4: Radical-trapping experiments.
Scheme 5: Proposed mechanism for the silver-catalyzed phosphonofluorination of alkynes.
Scheme 6: Attempted use of a suspected phosphonofluorination intermediate to synthesize a β-fluorovinylphosph...
Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles
- Wenbo Huang,
- Kaimei Wang,
- Ping Liu,
- Minghao Li,
- Shaoyong Ke and
- Yanlong Gu
Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241
- , aliphatic primary amines and ammonia, such as benzylamine and N-butylamine, were also examined as nitrogen donors; however, no desired product was detected. Then, we attempted to synthesize pharmaceutically active N-heterocyclic pyrrole derivatives with the aid of this three-component reaction. To our great
- aromatization to produce 5a. KI may play a key role in the last step, and we suspected that it can promote the removal of bromide. Although 5a can theoretically be synthesized through a three-component reaction of 1b, 2a, and an appropriate aldehyde, for example, acetaldehyde [50][51] owing to the insufficient
- . Direct synthesis of pyrrole-3-carboxamide derivatives. Plausible mechanism of the three-component reaction. Synthesis of polysubstituted pyrazolo[3,4-b]pyridine derivatives. Optimization of the conditions for the reaction between 1a, 2a, and 3a.a Supporting Information Supporting Information File 500
Graphical Abstract
Figure 1: Representative biologically active N-(hetero)aryl-4,5-unsubstituted pyrrole scaffolds.
Scheme 1: Typical routes to N-(heteroaryl)-4,5-unsubstituted pyrroles.
Scheme 2: Substrate scope of the pyrrole synthesis.
Scheme 3: Synthesis of N-heterocyclic pyrroles.
Scheme 4: Direct synthesis of pyrrole-3-carboxamide derivatives.
Scheme 5: Plausible mechanism of the three-component reaction.
Scheme 6: Synthesis of polysubstituted pyrazolo[3,4-b]pyridine derivatives.
A novel and robust heterogeneous Cu catalyst using modified lignosulfonate as support for the synthesis of nitrogen-containing heterocycles
- Bingbing Lai,
- Meng Ye,
- Ping Liu,
- Minghao Li,
- Rongxian Bai and
- Yanlong Gu
Beilstein J. Org. Chem. 2020, 16, 2888–2902, doi:10.3762/bjoc.16.238
- activity in organic reactions. Tricyclic indole alkaloids bearing 3,4-fused seven-membered rings have attracted much attention because of their interesting molecular architectures and important biological activities [32][33]. Here the three-component reaction of 4-aminoindole (1a), 4-methylbenzaldehyde (2a
- ) and diethyl acetylenedicarboxylate (3a) was performed to construct the seven-membered indole ring system with the aid of the LS-FAS-Cu catalyst, and the results are summarized in Table 1. At the beginning, the three-component reaction was conducted without the presence of any catalyst, but no products
- -Cu-promoted conditions as well, and gave the product 4o in 65% yield. The successful attempts in the three-component reaction of 4-aminoindoles (1a), alkynes and aldehydes indicate that the heterogeneous catalyst LS-FAS-Cu is competent for catalyzing nitrogen-containing heterocyclic compounds without
Graphical Abstract
Figure 1: Schematic illustration for the preparation of the catalyst in this work.
Figure 2: FTIR spectra of LS, LS-FAS, and LS-FAS-Cu.
Figure 3: Thermogravimetric weight loss of the obtained materials LS-FAS and LS-FAS-Cu.
Figure 4: FSEM imagine of LS-FAS-Cu in different scale label a) 1 μm, b) 200 nm; FTEM images of LS-FAS-Cu in ...
Figure 5: XPS spectra of LS-FAS-Cu in the regions of C 1s, O 1s, Cu 2p3/2 and Cu LMM (inset).
Scheme 1: Substrate scope of LS-FAS-Cu catalyzed three-component reactions of 4-aminoindoles, alkynes and ald...
Figure 6: Recyclability of LS-FAS-Cu, LS-FM-Cu and Resin-Cu in the reaction between compounds 1a, 2a and 3a.
Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination
- Yuqing Wang,
- Gaigai Wang,
- Anatoly A. Peshkov,
- Ruwei Yao,
- Muhammad Hasan,
- Manzoor Zaman,
- Chao Liu,
- Stepan Kashtanov,
- Olga P. Pereshivko and
- Vsevolod A. Peshkov
Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163
- associated with controlling their stereochemical outcome [33][34][35] severely restrict their applicability in medicinal chemistry [36]. The typical Passerini three-component reaction (P-3CR) of a carboxylic acid 1, an aldehyde 2, and an isocyanide 3 being conducted in a polar-aprotic solvent such as THF or
- structure of (S)-12e (slow enantiomer). Post-transformations of 2-oxo-aldehyde-derived Ugi adducts 8. Synthesis of 2-oxo-aldehyde-derived Ugi adducts. Asymmetric protocols for Passerini three-component reaction (P-3CR). Asymmetric protocols for Ugi four-component reaction (U-4CR) by Houk, Tan and co-workers
Graphical Abstract
Scheme 1: Post-transformations of 2-oxo-aldehyde-derived Ugi adducts 8.
Scheme 2: Synthesis of 2-oxo-aldehyde-derived Ugi adducts.
Figure 1: Molecular representation of the X-ray crystal structure of (S)-12e (slow enantiomer).
