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Search for "halide" in Full Text gives 369 result(s) in Beilstein Journal of Organic Chemistry. Showing first 200.
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
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
- 22 can be afforded easily (Scheme 7). This procedure offers a novel cyclization method with bifunctionalization, causing a multicomponent reaction of vinylaniline, halide, and sulfonylate to give corresponding indole derivatives. Furthermore, a wide variety of applicable substrates and good
- process, the authors supposed that it may facilitate single-electron transfer between biguanidine anion and perfluoroalkyl halide. By constructing two C–N bonds at the same time, the triazine heterocyclic structure that is commonly utilized in medical and material fields was accomplished by [5 + 1
- the EDA complex formed by aryl halide 106 and oxindole 107 under alkaline conditions allowed single-electron transfer under irradiation with light, eventually affording arylated oxidized indole product 108 (Scheme 37). This reaction provides an effective method to construct various 3-arylindoles with
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.
Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity
- Zbigniew Malinowski,
- Emilia Fornal,
- Agata Sumara,
- Renata Kontek,
- Karol Bukowski,
- Beata Pasternak,
- Dariusz Sroczyński,
- Joachim Kusz,
- Magdalena Małecka and
- Monika Nowak
Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50
- the coordination of the amine takes place after the oxidative addition of the organic halide to the palladium–ligand complex. Based on the analysis of our results we have concluded that in the case of systems 3, the order of reagent addition could have a significant impact on a proper course of the
Graphical Abstract
Figure 1: Structure of biologically active phthalazine derivatives.
Scheme 1: Synthetic route to aminophthalazinones 5 and 6.
Figure 2: Proposed catalytic cycles for the amination of 4-bromophthalazinones of type 3 (Phthal: phthalazino...
Scheme 2: Synthesis of 4-amino- and 4-polyaminophthalazinones 5 and 6 (the yields refer to the isolated compo...
Figure 3: The phthalazinone derivatives that were used to test the complexation of Cu(II) ions.
Scheme 3: The proposal of the fragmentation pathway of the Cu(II) complex with compound 7.
Figure 4: Structure of complex 17.
Figure 5: Molecular structure of complex 17 with atom numbering scheme. The anisotropic displacement paramete...
Figure 6: Determination of relative cell viability (% of control) in different cell lines (HT-29; PC-3 and L-...
Figure 7: Cytotoxic properties of the phthalazinone derivatives expressed as IC50 after 72 h of cell treatmen...
Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines
- Geetanjali S. Sontakke,
- Rahul K. Shukla and
- Chandra M. R. Volla
Beilstein J. Org. Chem. 2021, 17, 485–493, doi:10.3762/bjoc.17.42
- 3i and 3j were isolated in slightly lower yield (81% and 84%, respectively). Triazoles bearing halide substituents (Cl and Br) at the meta- or para-positions were also found to be viable substrates to afford the products 3k and 3l with 85–90% yield. Additionally, the reaction protocol is compatible
Graphical Abstract
Figure 1: Bioactive molecules containing the 2-aminoquinoline motif.
Scheme 1: C2-selective C–N bond formation of N-oxides.
Scheme 2: Substrate scope of N-sulfonyl-1,2,3-triazoles. Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol) an...
Scheme 3: Substrate scope of quinoline N-oxides. Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol) and DCE (2...
Scheme 4: Late-stage modification of natural products.
Scheme 5: Substrate scope for the reaction of substituted triazoles with isoquinoline N-oxide.
Scheme 6: Gram-scale and one-pot synthesis.
Scheme 7: Proposed mechanism.
CF3-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry
- Anthony J. Fernandes,
- Armen Panossian,
- Bastien Michelet,
- Agnès Martin-Mingot,
- Frédéric R. Leroux and
- Sébastien Thibaudeau
Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32
Graphical Abstract
Figure 1: Stabilizing interaction in the CF3CH2+ carbenium ion (top) and structure of the first observable fl...
Scheme 1: Isodesmic equations accounting for the destabilizing effect of the CF3 group. ΔE in kcal⋅mol−1, cal...
Scheme 2: Stabilizing effect of fluorine atoms by resonance electron donation in carbenium ions (δ in ppm).
Scheme 3: Direct in situ NMR observation of α-(trifluoromethyl)carbenium ion or protonated alcohols. Δδ = δ19...
Scheme 4: Reported 13C NMR chemical shifts for the α-(trifluoromethyl)carbenium ion 10c (δ in ppm).
Scheme 5: Direct NMR observation of α-(trifluoromethyl)carbenium ions in situ (δ in ppm).
Scheme 6: Illustration of the ion pair solvolysis mechanism for sulfonate 13f. YOH = solvent.
Figure 2: Solvolysis rate for 13a–i and 17.
Figure 3: Structures of allyl triflates 18 and 19 and allyl brosylate 20. Bs = p-BrC6H4SO2.
Figure 4: Structure of tosylate derivatives 21.
Figure 5: a) Structure of triflate derivatives 22. b) Stereochemistry outcomes of the reaction starting from (...
Scheme 7: Solvolysis reaction of naphthalene and anthracenyl derivatives 26 and 29.
Figure 6: Structure of bisarylated derivatives 34.
Figure 7: Structure of bisarylated derivatives 36.
Scheme 8: Reactivity of 9c in the presence of a Brønsted acid.
Scheme 9: Cationic electrocyclization of 38a–c under strongly acidic conditions.
Scheme 10: Brønsted acid-catalyzed synthesis of indenes 42 and indanes 43.
Scheme 11: Reactivity of sulfurane 44 in triflic acid.
Scheme 12: Solvolysis of triflate 45f in alcoholic solvents.
Scheme 13: Synthesis of labeled 18O-52.
Scheme 14: Reactivity of sulfurane 53 in triflic acid.
Figure 8: Structure of tosylates 56 and 21f.
Scheme 15: Resonance forms in benzylic carbenium ions.
Figure 9: Structure of pyrrole derivatives 58 and 59.
Scheme 16: Resonance structure 60↔60’.
Scheme 17: Ga(OTf)3-catalyzed synthesis of 3,3’- and 3,6’-bis(indolyl)methane from trifluoromethylated 3-indol...
Scheme 18: Proposed reaction mechanism.
Scheme 19: Metal-free 1,2-phosphorylation of 3-indolylmethanols.
Scheme 20: Superacid-mediated arylation of thiophene derivatives.
Scheme 21: In situ mechanistic NMR investigations.
Scheme 22: Proposed mechanisms for the prenyltransferase-catalyzed condensation.
Scheme 23: Influence of a CF3 group on the allylic SN1- and SN2-mechanism-based reactions.
Scheme 24: Influence of the CF3 group on the condensation reaction.
Scheme 25: Solvolysis of 90 in TFE.
Scheme 26: Solvolysis of allyl triflates 94 and 97 and isomerization attempt of 96.
Scheme 27: Proposed mechanism for the formation of 95.
Scheme 28: Formation of α-(trifluoromethyl)allylcarbenium ion 100 in a superacid.
Scheme 29: Lewis acid activation of CF3-substituted allylic alcohols.
Scheme 30: Bimetallic-cluster-stabilized α-(trifluoromethyl)carbenium ions.
Scheme 31: Reactivity of cluster-stabilized α-(trifluoromethyl)carbenium ions.
Scheme 32: α-(Trifluoromethyl)propargylium ion 122↔122’ generated from silyl ether 120 in a superacid.
Scheme 33: Formation of α-(trifluoromethyl)propargylium ions from CF3-substituted propargyl alcohols.
Scheme 34: Direct NMR observation of the protonation of some trifluoromethyl ketones in situ and the correspon...
Scheme 35: Selected resonance forms in protonated fluoroketone derivatives.
Scheme 36: Acid-catalyzed Friedel–Crafts reactions of trifluoromethyl ketones 143a,b and 147a–c.
Scheme 37: Enantioselective hydroarylation of CF3-substituted ketones.
Scheme 38: Acid-catalyzed arylation of ketones 152a–c.
Scheme 39: Reactivity of 156 in a superacid.
Scheme 40: Reactivity of α-CF3-substituted heteroaromatic ketones and alcohols as well as 1,3-diketones.
Scheme 41: Reactivity of 168 with benzene in the presence of a Lewis or Brønsted acid.
Scheme 42: Acid-catalyzed three-component asymmetric reaction.
Scheme 43: Anodic oxidation of amines 178a–c and proposed mechanism.
Scheme 44: Reactivity of 179b in the presence of a strong Lewis acid.
Scheme 45: Trifluoromethylated derivatives as precursors of trifluoromethylated iminium ions.
Scheme 46: Mannich reaction with trifluoromethylated hemiaminal 189.
Scheme 47: Suitable nucleophiles reacting with 192 after Lewis acid activation.
Scheme 48: Strecker reaction involving the trifluoromethylated iminium ion 187.
Scheme 49: Reactivity of 199 toward nucleophiles.
Scheme 50: Reactivity of 204a with benzene in the presence of a Lewis acid.
Scheme 51: Reactivity of α-(trifluoromethyl)-α-chloro sulfides in the presence of strong Lewis acids.
Scheme 52: Anodic oxidation of sulfides 213a–h and Pummerer rearrangement.
Scheme 53: Mechanism for the electrochemical oxidation of the sulfide 213a.
Scheme 54: Reactivity of (trifluoromethyl)diazomethane (217a) in HSO3F.
Figure 10: a) Structure of diazoalkanes 217a–c and b) rate-limiting steps of their decomposition.
Scheme 55: Deamination reaction of racemic 221 and enantioenriched (S)-221.
Scheme 56: Deamination reaction of labeled 221-d2. Elimination products were formed in this reaction, the yiel...
Scheme 57: Deamination reaction of 225-d2. Elimination products were also formed in this reaction in undetermi...
Scheme 58: Formation of 229 from 228 via 1,2-H-shift.
Scheme 59: Deamination reaction of 230. Elimination products were formed in this reaction, the yield of which ...
Scheme 60: Deamination of several diazonium ions. Elimination products were formed in these reactions, the yie...
Scheme 61: Solvolysis reaction mechanism of alkyl tosylates.
Scheme 62: Solvolysis outcome for the tosylates 248 and 249 in HSO3FSbF5.
Figure 11: Solvolysis rate of 248, 249, 252, and 253 in 91% H2SO4.
Scheme 63: Illustration of the reaction pathways. TsCl, pyridine, −5 °C (A); 98% H2SO4, 30 °C (B); 98% H2SO4, ...
Scheme 64: Proposed solvolysis mechanism for the aliphatic tosylate 248.
Scheme 65: Solvolysis of the derivatives 259 and 260.
Scheme 66: Solvolysis of triflate 261. SOH = solvent.
Scheme 67: Intramolecular Friedel–Crafts alkylations upon the solvolysis of triflates 264 and 267.
Scheme 68: α-CF3-enhanced γ-silyl elimination of cyclobutyltosylates 270a,b.
Scheme 69: γ-Silyl elimination in the synthesis of a large variety of CF3-substituted cyclopropanes. Pf = pent...
Scheme 70: Synthetic pathways to 281. aNMR yields.
Scheme 71: The cyclopropyl-substituted homoallylcyclobutylcarbenium ion manifold.
Scheme 72: Reactivity of CF3-substituted cyclopropylcarbinyl derivatives 287a–c. LG = leaving group.
Scheme 73: Reactivity of CF3-substituted cyclopropylcarbinyl derivatives 291a–c.
Scheme 74: Superacid-promoted dimerization or TFP.
Scheme 75: Reactivity of TFP in a superacid.
Scheme 76: gem-Difluorination of α-fluoroalkyl styrenes via the formation of a “hidden” α-RF-substituted carbe...
Scheme 77: Solvolysis of CF3-substituted pentyne 307.
Scheme 78: Photochemical rearrangement of 313.
Figure 12: Structure of 2-norbornylcarbenium ion 318 and argued model for the stabilization of this cation.
Figure 13: Structures and solvolysis rate (TFE, 25 °C) of the sulfonates 319–321. Mos = p-MeOC6H4SO2.
Scheme 79: Mechanism for the solvolysis of 323. SOH = solvent.
Scheme 80: Products formed by the hydrolysis of 328.
Scheme 81: Proposed carbenium ion intermediates in an equilibrium during the solvolysis of tosylates 328, 333,...
The preparation and properties of 1,1-difluorocyclopropane derivatives
- Kymbat S. Adekenova,
- Peter B. Wyatt and
- Sergazy M. Adekenov
Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25
- halodifluoromethanes and alkenes (Scheme 2). The elimination of hydrogen halide from the halodifluoromethane under basic conditions (metal alkoxide or alkyllithium) generated difluorocarbene [14][15]. The low yields of the product have been attributed to the facile addition of the strong bases to difluorocarbene. The
- yields were best in the reactions with electron-rich alkenes and when a low concentration of the base was used to minimize the destruction of difluorocarbene. The use of oxirane or epichlorohydrin as hydrogen halide scavengers avoided the need for a stoichiometric amount of the strong base [16][17]. The
- amounts of halide sources (e.g., tetramethylammonium chloride or tetrabutylammonium bromide). Compared with the difluoromethylenation protocols using TFDA (25), MDFA (30), or TMSCF3 (31), the application of BrCF2SiMe3 has been claimed to be safer and more convenient for large-scale application because of
Graphical Abstract
Scheme 1: Synthesis of 1,1-difluoro-2,3-dimethylcyclopropane (2).
Scheme 2: Cyclopropanation via dehydrohalogenation of chlorodifluoromethane.
Scheme 3: Difluorocyclopropanation of methylstyrene 7 using dibromodifluoromethane and zinc.
Scheme 4: Synthesis of difluorocyclopropanes from the reaction of dibromodifluoromethane and triphenylphosphi...
Scheme 5: Generation of difluorocarbene in a catalytic two-phase system and its addition to tetramethylethyle...
Scheme 6: The reaction of methylstyrene 7 with chlorodifluoromethane (11) in the presence of a tetraarylarson...
Scheme 7: Pyrolysis of sodium chlorodifluoroacetate (12) in refluxing diglyme in the presence of alkene 13.
Scheme 8: Synthesis of boron-substituted gem-difluorocyclopropanes 16.
Scheme 9: Addition of sodium bromodifluoroacetate (17) to alkenes.
Scheme 10: Addition of sodium bromodifluoroacetate (17) to silyloxy-substituted cyclopropanes 20.
Scheme 11: Synthesis of difluorinated nucleosides.
Scheme 12: Addition of butyl acrylate (26) to difluorocarbene generated from TFDA (25).
Scheme 13: Addition of difluorocarbene to propargyl esters 27 and conversion of the difluorocyclopropenes 28 t...
Scheme 14: The generation of difluorocyclopropanes using MDFA 30.
Scheme 15: gem-Difluorocyclopropanation of styrene (32) using difluorocarbene generated from TMSCF3 (31) under...
Scheme 16: Synthesis of a gem-difluorocyclopropane derivative using HFPO (41) as a source of difluorocarbene.
Scheme 17: Cyclopropanation of (Z)-2-butene in the presence of difluorodiazirine (44).
Scheme 18: The cyclopropanation of 1-octene (46) using Seyferth's reagent (45) as a source of difluorocarbene.
Scheme 19: Alternative approaches for the difluorocarbene synthesis from trimethyl(trifluoromethyl)tin (48).
Scheme 20: Difluorocyclopropanation of cyclohexene (49).
Scheme 21: Synthesis of difluorocyclopropane derivative 53 using bis(trifluoromethyl)cadmium (51) as the diflu...
Scheme 22: Addition of difluorocarbene generated from tris(trifluoromethyl)bismuth (54).
Scheme 23: Addition of a stable (trifluoromethyl)zinc reagent to styrenes.
Scheme 24: The preparation of 2,2-difluorocyclopropanecarboxylic acids of type 58.
Scheme 25: Difluorocyclopropanation via Michael cyclization.
Scheme 26: Difluorocyclopropanation using N-acylimidazolidinone 60.
Scheme 27: Difluorocyclopropanation through the cyclization of phenylacetonitrile (61) and 1,2-dibromo-1,1-dif...
Scheme 28: gem-Difluoroolefins 64 for the synthesis of functionalized cyclopropanes 65.
Scheme 29: Preparation of aminocyclopropanes 70.
Scheme 30: Synthesis of fluorinated methylenecyclopropane 74 via selenoxide elimination.
Scheme 31: Reductive dehalogenation of (1R,3R)-75.
Scheme 32: Synthesis of chiral monoacetates by lipase catalysis.
Scheme 33: Transformation of (±)-trans-81 using Rhodococcus sp. AJ270.
Scheme 34: Transformation of (±)-trans-83 using Rhodococcus sp. AJ270.
Scheme 35: Hydrogenation of difluorocyclopropenes through enantioselective hydrocupration.
Scheme 36: Enantioselective transfer hydrogenation of difluorocyclopropenes with a Ru-based catalyst.
Scheme 37: The thermal transformation of trans-1,2-dichloro-3,3-difluorocyclopropane (84).
Scheme 38: cis–trans-Epimerization of 1,1-difluoro-2,3-dimethylcyclopropane.
Scheme 39: 2,2-Difluorotrimethylene diradical intermediate.
Scheme 40: Ring opening of stereoisomers 88 and 89.
Scheme 41: [1,3]-Rearrangement of alkenylcyclopropanes 90–92.
Scheme 42: Thermolytic rearrangement of 2,2-difluoro-1-vinylcyclopropane (90).
Scheme 43: Thermal rearrangement for ethyl 3-(2,2-difluoro)-3-phenylcyclopropyl)acrylates 93 and 95.
Scheme 44: Possible pathways of the ring opening of 1,1-difluoro-2-vinylcyclopropane.
Scheme 45: Equilibrium between 1,1-difluoro-2-methylenecyclopropane (96) and (difluoromethylene)cyclopropane 97...
Scheme 46: Ring opening of substituted 1,1-difluoro-2,2-dimethyl-3-methylenecyclopropane 98.
Scheme 47: 1,1-Difluorospiropentane rearrangement.
Scheme 48: Acetolysis of (2,2-difluorocyclopropyl)methyl tosylate (104) and (1,1-difluoro-2-methylcyclopropyl)...
Scheme 49: Ring opening of gem-difluorocyclopropyl ketones 106 and 108 by thiolate nucleophiles.
Scheme 50: Hydrolysis of gem-difluorocyclopropyl acetals 110.
Scheme 51: Ring-opening reaction of 2,2-difluorocyclopropyl ketones 113 in the presence of ionic liquid as a s...
Scheme 52: Ring opening of gem-difluorocyclopropyl ketones 113a by MgI2-initiated reaction with diarylimines 1...
Scheme 53: Ring-opening reaction of gem-difluorocyclopropylstannanes 117.
Scheme 54: Preparation of 1-fluorovinyl vinyl ketone 123 and the synthesis of 2-fluorocyclopentenone 124. TBAT...
Scheme 55: Iodine atom-transfer ring opening of 1,1-difluoro-2-(1-iodoalkyl)cyclopropanes 125a–c.
Scheme 56: Ring opening of bromomethyl gem-difluorocyclopropanes 130 and formation of gem-difluoromethylene-co...
Scheme 57: Ring-opening aerobic oxidation reaction of gem-difluorocyclopropanes 132.
Scheme 58: Dibrominative ring-opening functionalization of gem-difluorocyclopropanes 134.
Scheme 59: The selective formation of (E,E)- and (E,Z)-fluorodienals 136 and 137 from difluorocyclopropyl acet...
Scheme 60: Proposed mechanism for the reaction of difluoro(methylene)cyclopropane 139 with Br2.
Scheme 61: Thermal rearrangement of F2MCP 139 and iodine by CuI catalysis.
Scheme 62: Synthesis of 2-fluoropyrroles 142.
Scheme 63: Ring opening of gem-difluorocyclopropyl ketones 143 mediated by BX3.
Scheme 64: Lewis acid-promoted ring-opening reaction of 2,2-difluorocyclopropanecarbonyl chloride (148).
Scheme 65: Ring-opening reaction of the gem-difluorocyclopropyl ketone 106 by methanolic KOH.
Scheme 66: Hydrogenolysis of 1,1-difluoro-3-methyl-2-phenylcyclopropane (151).
Scheme 67: Synthesis of monofluoroalkenes 157.
Scheme 68: The stereoselective Ag-catalyzed defluorinative ring-opening diarylation of 1-trimethylsiloxy-2,2-d...
Scheme 69: Synthesis of 2-fluorinated allylic compounds 162.
Scheme 70: Pd-catalyzed cross-coupling reactions of gem-difluorinated cyclopropanes 161.
Scheme 71: The (Z)-selective Pd-catalyzed ring-opening sulfonylation of 2-(2,2-difluorocyclopropyl)naphthalene...
Figure 1: Structures of zosuquidar hydrochloride and PF-06700841.
Scheme 72: Synthesis of methylene-gem-difluorocyclopropane analogs of nucleosides.
Figure 2: Anthracene-difluorocyclopropane hybrid derivatives.
Figure 3: Further examples of difluorcyclopropanes in modern drug discovery.
Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols
- Armin Ariamajd,
- Nils J. Gerwien,
- Benjamin Schwabe,
- Stefan Dix and
- Matthew N. Hopkinson
Beilstein J. Org. Chem. 2021, 17, 83–88, doi:10.3762/bjoc.17.8
- substitution reactions of this type are synthetically appealing as they avoid pre-generation of an active electrophile such as an alkyl halide. A selection of benzylic alcohols 2 was reacted under the standard conditions with BT-SC2F5 (1.25 equiv) and NEt(iPr)2 (2 equiv) in MeCN at −40 °C, providing the
- alcohols, thus avoiding the pre-formation of an alkyl halide. This straight-forward route should inspire further investigations of perfluoroalkylthio groups in pharmaceutical, agrochemical and materials science. Synthetic routes towards perfluoroalkyl thioethers. Two-step synthesis of BT-SRF reagents from
Graphical Abstract
Scheme 1: Synthetic routes towards perfluoroalkyl thioethers.
Scheme 2: Two-step synthesis of BT-SRF reagents from MBT.
Scheme 3: Plausible mechanism for the formation of thioether 3 and thionoester 4.
Scheme 4: Scope of the deoxygenative perfluoroalkylthiolation reaction using BT-SC2F5 and BT-SC3F7.
Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction
- Vyacheslav I. Supranovich,
- Igor A. Dmitriev and
- Alexander D. Dilman
Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260
- photocatalyst and stoichiometric quantities (1.2 equiv) of a reducing system (ascorbic acid/collidine). In this reaction no products were formed with reactant 2a remaining unconsumed (Table 1). To obtain a more reactive fluorinated halide, the bromine atom residing at the fluorinated moiety was exchanged for
Graphical Abstract
Scheme 1: The construction of tetrafluorinated piperidines from nitrones.
Scheme 2: The scope of the annelation reaction for the synthesis of piperidines. Isolated yields are shown. a...
Scheme 3: The proposed mechanism of the photoredox annelation reaction (asc = ascorbic acid).
Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation
- Jennifer Frommer and
- Sabine Müller
Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234
- halide to iodine, taking into account that direct iodination of purines has been claimed being troublesome [26], although not impossible [27]. For C8-iodination of adenosine, first the hydroxy groups at the sugar moiety were protected with tert-butyldimethylsilyl (TBDMS) groups. The silylated nucleoside
Graphical Abstract
Scheme 1: Synthesis of a C8-linker-modified adenosine derivative. (a) 4 equiv TBDMS-Cl, 5 equiv imidazole, DM...
Figure 1: Characterization and assignment of the TBDMS isomers via HSQC (red) and HMBC (blue) NMR measurement...
Scheme 2: New synthetic route to the C8-linker modified adenosine building block. (a) i) 1.2 equiv di-tert-bu...
Dirhamnolipid ester – formation of reverse wormlike micelles in a binary (primerless) system
- David Liese,
- Hans Henning Wenk,
- Xin Lu,
- Jochen Kleinen and
- Gebhard Haberhauer
Beilstein J. Org. Chem. 2020, 16, 2820–2830, doi:10.3762/bjoc.16.232
- chain length without the production of side products (Scheme 1). Under mild and basic conditions, with this SN2 reaction of the dirhamnolipid and any primary alkyl halide, the desired product was obtained with a high yield ranging from 70–85%. Also, a gemini-like structure 7 was synthesized. Solubility
Graphical Abstract
Figure 1: Chemical structure of dirhamnolipid 1.
Scheme 1: Synthesis of the dirhamnolipid esters and the chemical structure of 7.
Figure 2: Solubility of the dirhamnolipid esters in various solvents (+ = soluble, − = insoluble, G = gel).
Figure 3: Phase transition temperature for the dirhamnolipid esters in toluene while heating (TGS, blue) and ...
Figure 4: Amplitude sweep: double logarithmic plot of the dynamic moduli against the amplitude (deformation) ...
Figure 5: Frequency sweep: double logarithmic plot of the dynamic moduli against the frequency for the dirham...
Figure 6: Double logarithmic plot of (a) the plateau modulus G0 and (b) the relaxation time τR against the co...
Figure 7: Semilogarithmic plot of (a) G0/G''min, (b) η0, and (c) τR against the inverse absolute temperature ...
Figure 8: Polarized optical microscopy (POM) images of the 2/toluene system (5 wt %) with crossed polarizers ...
Figure 9: Schematic representation of the formation of RWLM by dirhamnolipid esters.
Synthesis of novel fluorinated building blocks via halofluorination and related reactions
- Attila Márió Remete,
- Tamás T. Novák,
- Melinda Nonn,
- Matti Haukka,
- Ferenc Fülöp and
- Loránd Kiss
Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208
- steric hindrance – and 33% unreacted starting material was recovered from the iodofluorination reaction mixture. In order to study the synthetic usefulness of the halofluorinated products, E2 hydrogen halide elimination was attempted. Since bromide and iodide are much better leaving groups than fluoride
- , the selective elimination of the former halogens was expected. Taking into account the stereochemical requirements of the E2 elimination (the halide group and the β-hydrogen atom should be antiperiplanar relative to each other), the limited availability of the compound (rac)-5b, and Bredt’s rule
- upon the intramolecular nucleophilic attack by the alkyl halide (Scheme 16). The reaction of the compound (rac)-6b is less direct. According to the above pathway, the formation of the compound (rac)-T10 would be expected (Scheme 17). In order to generate the final product (rac)-27, a base-catalyzed
Graphical Abstract
Scheme 1: Proposed outcome of the halofluorination of (rac)-1. Only the main conformers of (rac)-1 and (rac)-...
Scheme 2: Halofluorination reactions of the trans-diester (rac)-1.
Scheme 3: Probable outcomes of the halofluorination of 4. Both conformers of the compounds 4, (rac)-T2a,b, an...
Scheme 4: Halofluorination reactions of the cis-diester 4. Important NOESY interactions are indicated by two-...
Scheme 5: Halofluorination reactions of the cis-tetrahydrophthalic imide derivative 7.
Scheme 6: Synthesis and halofluorination of the trans-imide (rac)-10.
Figure 1: Crystal structure of (rac)-11b.
Scheme 7: Synthesis of the cyclic carbamide (rac)-13.
Scheme 8: Halofluorination reactions of the γ-lactam (rac)-14. Relevant NOESY interactions are indicated by t...
Figure 2: Crystal structure of the product (rac)-15a.
Figure 3: Crystal structure of the product (rac)-15b.
Scheme 9: Reactions of the diester 16 with NBS or NIS in the presence or absence of Deoxo-Fluor®.
Scheme 10: Formation of the halolactons (rac)-17a,b. The initial attack of the halogen cation occurs at the st...
Scheme 11: Unsuccessful halofluorination of the bicyclic diester 18.
Scheme 12: Halofluorination reactions of the rigid tricyclic imine 19. The relevant NOESY interactions are mar...
Scheme 13: Mechanism of the halofluorination reactions of the substrate 19. X = Br (compounds a), I (compounds...
Scheme 14: Synthesis and halofluorination of the imide 24.
Scheme 15: Cyclizations of halofluorinated diesters with potassium tert-butoxide. Relevant NOESY interactions ...
Scheme 16: Mechanism of the reaction of the cyclopropanation of the compounds (rac)-2a,b and (rac)-5a with t-B...
Scheme 17: Presumed mechanism of the reaction of the compound (rac)-6b with t-BuOK.
Scheme 18: Cyclizations of halofluorinated tetrahydrophthalimides with DBU. Relevant NOESY interactions are ma...
Scheme 19: Mechanism for the formation of (rac)-28 from (rac)-11a,b. Although the formation of the compound (r...
Scheme 20: Fluoroselenations of the cyclohexenedicarboxylates (rac)-1 and 4.
Scheme 21: PhSe+-induced lactonization of the diester 16. Relevant NOESY interactions are marked with two-head...
Scheme 22: Oxidation of the fluoroselenide (rac)-30 under acidic and basic conditions.
Scheme 23: Oxidation of the fluoroselenide mixture (rac)-31 under acidic and basic conditions.
Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors
- Emine Kayahan,
- Mathias Jacobs,
- Leen Braeken,
- Leen C.J. Thomassen,
- Simon Kuhn,
- Tom van Gerven and
- M. Enis Leblebici
Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202
- , a microcapillary reactor (1/6” OD, 3.5 mL reactor volume) that was wrapped around a metal halide UV lamp was scaled up by using several strategies together. Rather than splitting up the reaction medium into many photoreactors, the photoreactors were numbered up by adding them in series (Figure 3b
Graphical Abstract
Figure 1: The momentum transport affects the mass transfer and the light field. All transport phenomena need ...
Figure 2: Common photomicroreactor designs: (a) Straight channel, (b) serpentine channel, (c) square serpenti...
Figure 3: Benchmarked photoreactors: (a) Microcapillaries in parallel, (b) microcapillaries in series, (c) fl...
Figure 4: Photochemical reactions that are detailed in Table 1.
Figure 5: Structured reactors designed for enhancing the mass transfer: (a) Packed bed photoreactor, (b) mono...
Figure 6: Comparison of the LED board designs of photomicroreactors: (a) CC array design, (b) MC array design...
Figure 7: Illustration of the light scattering phenomenon inside a photocatalytic flow reactor.
Figure 8: Efficiency of the absorption process in scattering situations with respect to pure absorption situa...
Figure 9: Different types of distributors: (a) Traditional or consecutive manifold, (b) bifurcation unit dist...
Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents
- Paola Vitale,
- Luciana Cicco,
- Ilaria Cellamare,
- Filippo M. Perna,
- Antonio Salomone and
- Vito Capriati
Beilstein J. Org. Chem. 2020, 16, 1915–1923, doi:10.3762/bjoc.16.158
- cross-coupling reactions. A 4-fluoro-substituted phenacyl chloride as well as a bromomethyl 2-naphthyl ketone proved to be competent substrates as well, thus furnishing the corresponding imidazoles 3i/3i' and 3j in 67–87% yield. Conversely, a phenacyl halide decorated with an additional phenyl group at
Graphical Abstract
Scheme 1: One-pot synthesis of 2,5-diarylpyrazines (A) (path a) or 2-aroyl-(4 or 5)-aryl-(1H)-imidazoles (B) ...
Scheme 2: Transformation of phenacyl bromide (1a) in ChCl/Gly into phenacyl azide (2a) and 2-benzoyl-(4 or 5)...
Scheme 3: Synthesis of 2-aroyl-(4 or 5)-aryl-(1H)-imidazoles 3. Scope of the reaction. Typical conditions: 1 ...
Scheme 4: Proposed mechanism for the formation of 2-aroyl-(4 or 5)-aryl-(1H)-imidazoles 3/3' from α-phenacyl ...
Scheme 5: Proposed mechanism for the formation of 2-benzoyl-(4 or 5)-phenyl-(1H)-imidazoles 3a/3a' and 2,4-di...
Scheme 6: Scope of the synthesis of 2,4-diaroyl-6-arylpyrimidines 7. Typical conditions: 2 (0.3 mmol), Et3N (...
When metal-catalyzed C–H functionalization meets visible-light photocatalysis
- Lucas Guillemard and
- Joanna Wencel-Delord
Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147
Graphical Abstract
Figure 1: Concept of dual synergistic catalysis.
Figure 2: Classification of catalytic systems involving two catalysts.
Figure 3: General mechanism for the dual nickel/photoredox catalytic system.
Figure 4: General mechanisms for C–H activation catalysis involving different reoxidation strategies.
Figure 5: Indole synthesis via dual C–H activation/photoredox catalysis.
Figure 6: Proposed mechanism for the indole synthesis via dual catalysis.
Figure 7: Oxidative Heck reaction on arenes via the dual catalysis.
Figure 8: Proposed mechanism for the Heck reaction on arenes via dual catalysis.
Figure 9: Oxidative Heck reaction on phenols via the dual catalysis.
Figure 10: Proposed mechanism for the Heck reaction on phenols via dual catalysis.
Figure 11: Carbazole synthesis via dual C–H activation/photoredox catalysis.
Figure 12: Proposed mechanism for the carbazole synthesis via dual catalysis.
Figure 13: Carbonylation of enamides via the dual C–H activation/photoredox catalysis.
Figure 14: Proposed mechanism for carbonylation of enamides via dual catalysis.
Figure 15: Annulation of benzamides via the dual C–H activation/photoredox catalysis.
Figure 16: Proposed mechanism for the annulation of benzamides via dual catalysis.
Figure 17: Synthesis of indoles via the dual C–H activation/photoredox catalysis.
Figure 18: Proposed mechanism for the indole synthesis via dual catalysis.
Figure 19: General concept of dual catalysis merging C–H activation and photoredox catalysis.
Figure 20: The first example of dual catalysis merging C–H activation and photoredox catalysis.
Figure 21: Proposed mechanism for the C–H arylation with diazonium salts via dual catalysis.
Figure 22: Dual catalysis merging C–H activation/photoredox using diaryliodonium salts.
Figure 23: Direct arylation via the dual catalytic system reported by Xu.
Figure 24: Direct arylation via dual catalytic system reported by Balaraman.
Figure 25: Direct arylation via dual catalytic system reported by Guo.
Figure 26: C(sp3)–H bond arylation via the dual Pd/photoredox catalytic system.
Figure 27: Acetanilide derivatives acylation via the dual C–H activation/photoredox catalysis.
Figure 28: Proposed mechanism for the C–H acylation with α-ketoacids via dual catalysis.
Figure 29: Acylation of azobenzenes via the dual catalysis C–H activation/photoredox.
Figure 30: C2-acylation of indoles via the dual C–H activation/photoredox catalysis.
Figure 31: Proposed mechanism for the C2-acylation of indoles with aldehydes via dual catalysis.
Figure 32: C2-acylation of indoles via the dual C–H activation/photoredox catalysis.
Figure 33: Perfluoroalkylation of arenes via the dual C–H activation/photoredox catalysis.
Figure 34: Proposed mechanism for perfluoroalkylation of arenes via dual catalysis.
Figure 35: Sulfonylation of 1-naphthylamides via the dual C–H activation/photoredox catalysis.
Figure 36: Proposed mechanism for sulfonylation of 1-naphthylamides via dual catalysis.
Figure 37: meta-C–H Alkylation of arenes via visible-light metallaphotocatalysis.
Figure 38: Alternative procedure for meta-C–H alkylation of arenes via metallaphotocatalysis.
Figure 39: Proposed mechanism for meta-C–H alkylation of arenes via metallaphotocatalysis.
Figure 40: C–H borylation of arenes via visible-light metallaphotocatalysis.
Figure 41: Proposed mechanism for C–H borylation of arenes via visible-light metallaphotocatalysis.
Figure 42: Undirected C–H aryl–aryl cross coupling via dual gold/photoredox catalysis.
Figure 43: Proposed mechanism for the undirected C–H aryl–aryl cross-coupling via dual catalysis.
Figure 44: Undirected C–H arylation of (hetero)arenes via dual manganese/photoredox catalysis.
Figure 45: Proposed mechanism for the undirected arylation of (hetero)arenes via dual catalysis.
Figure 46: Photoinduced C–H arylation of azoles via copper catalysis.
Figure 47: Photo-induced C–H chalcogenation of azoles via copper catalysis.
Figure 48: Decarboxylative C–H adamantylation of azoles via dual cobalt/photoredox catalysis.
Figure 49: Proposed mechanism for the C–H adamantylation of azoles via dual catalysis.
Figure 50: General mechanisms for the “classical” (left) and Cu-free variant (right) Sonogoshira reaction.
Figure 51: First example of a dual palladium/photoredox catalysis for Sonogashira-type couplings.
Figure 52: Arylation of terminal alkynes with diazonium salts via dual gold/photoredox catalysis.
Figure 53: Proposed mechanism for the arylation of terminal alkynes via dual catalysis.
Figure 54: C–H Alkylation of alcohols promoted by H-atom transfer (HAT).
Figure 55: Proposed mechanism for the C–H alkylation of alcohols promoted by HAT.
Figure 56: C(sp3)–H arylation of latent nucleophiles promoted by H-atom transfer.
Figure 57: Proposed mechanism for the C(sp3)–H arylation of latent nucleophiles promoted by HAT.
Figure 58: Direct α-arylation of alcohols promoted by H-atom transfer.
Figure 59: Proposed mechanism for the direct α-arylation of alcohols promoted by HAT.
Figure 60: C–H arylation of amines via dual Ni/photoredox catalysis.
Figure 61: Proposed mechanism for the C–H arylation of amines via dual Ni/photoredox catalysis.
Figure 62: C–H functionalization of nucleophiles via excited ketone/nickel dual catalysis.
Figure 63: Proposed mechanism for the C–H functionalization enabled by excited ketones.
Figure 64: Selective sp3–sp3 cross-coupling promoted by H-atom transfer.
Figure 65: Proposed mechanism for the selective sp3–sp3 cross-coupling promoted by HAT.
Figure 66: Direct C(sp3)–H acylation of amines via dual Ni/photoredox catalysis.
Figure 67: Proposed mechanism for the C–H acylation of amines via dual Ni/photoredox catalysis.
Figure 68: C–H hydroalkylation of internal alkynes via dual Ni/photoredox catalysis.
Figure 69: Proposed mechanism for the C–H hydroalkylation of internal alkynes.
Figure 70: Alternative procedure for the C–H hydroalkylation of ynones, ynoates, and ynamides.
Figure 71: Allylic C(sp3)–H activation via dual Ni/photoredox catalysis.
Figure 72: Proposed mechanism for the allylic C(sp3)–H activation via dual Ni/photoredox catalysis.
Figure 73: Asymmetric allylation of aldehydes via dual Cr/photoredox catalysis.
Figure 74: Proposed mechanism for the asymmetric allylation of aldehydes via dual catalysis.
Figure 75: Aldehyde C–H functionalization promoted by H-atom transfer.
Figure 76: Proposed mechanism for the C–H functionalization of aldehydes promoted by HAT.
Figure 77: Direct C–H arylation of strong aliphatic bonds promoted by HAT.
Figure 78: Proposed mechanism for the C–H arylation of strong aliphatic bonds promoted by HAT.
Figure 79: Direct C–H trifluoromethylation of strong aliphatic bonds promoted by HAT.
Figure 80: Proposed mechanism for the C–H trifluoromethylation of strong aliphatic bonds.
Pauson–Khand reaction of fluorinated compounds
- Jorge Escorihuela,
- Daniel M. Sedgwick,
- Alberto Llobat,
- Mercedes Medio-Simón,
- Pablo Barrio and
- Santos Fustero
Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138
- (Scheme 23) [59]. The authors rationalized the formation of 45 by considering that the inherent weakening of the C—X bond going down the halogen series may favor the generation of radical A with chloride and bromide derivatives, especially given the tertiary position of the halide and the stoichiometric
Graphical Abstract
Scheme 1: Schematic representation of the Pauson–Khand reaction.
Scheme 2: Substrates included in this review.
Scheme 3: Commonly accepted mechanism for the Pauson–Khand reaction.
Scheme 4: Regioselectivity of the PKR.
Scheme 5: Variability at the acetylenic and olefinic counterpart.
Scheme 6: Pauson–Khand reaction of fluoroolefinic enynes reported by the group of Ishizaki [46].
Scheme 7: PKR of enynes bearing fluorinated groups on the alkynyl moiety, reported by the group of Ishizaki [46]....
Scheme 8: Intramolecular PKR of 1,7-enynes reported by the group of Billard [47].
Scheme 9: Intramolecular PKR of 1,7-enynes reported by the group of Billard [48].
Scheme 10: Intramolecular PKR of 1,7-enynes by the group of Bonnet-Delpon [49]. Reaction conditions: i) Co(CO)8 (1...
Scheme 11: Intramolecular PKR of 1,6-enynes reported by the group of Ichikawa [50].
Scheme 12: Intramolecular Rh(I)-catalyzed PKR reported by the group of Hammond [52].
Scheme 13: Intramolecular PKR of allenynes reported by the group of Osipov [53].
Scheme 14: Intramolecular PKR of 1,7-enynes reported by the group of Osipov [53].
Scheme 15: Intramolecular PKR of fluorine-containing 1,6-enynes reported by the Konno group [54].
Scheme 16: Diastereoselective PKR with enantioenriched fluorinated enynes 34 [55].
Scheme 17: Intramolecular PKR reported by the group of Martinez-Solorio [56].
Scheme 18: Fluorine substitution at the olefinic counterpart.
Scheme 19: Synthesis of fluorinated enynes 37 [59].
Scheme 20: Fluorine-containing substrates in PKR [59].
Scheme 21: Pauson Khand reaction for fluorinated enynes by the Fustero group: scope and limitations [59].
Scheme 22: Synthesis of chloro and bromo analogues [59].
Scheme 23: Dimerization pathway [59].
Scheme 24: Synthesis of fluorine-containing N-tethered 1,7-enynes [61].
Scheme 25: Intramolecular PKR of chiral N-tethered fluorinated 1,7-enynes [61].
Scheme 26: Examples of further modifications to the Pauson−Khand adducts [61].
Scheme 27: Asymmetric synthesis the fluorinated enynes 53.
Scheme 28: Intramolecular PKR of chiral N-tethered 1,7-enynes 53 [64].
Scheme 29: Intramolecular PKR of chiral N-tethered 1,7-enyne bearing a vinyl fluoride [64].
Scheme 30: Catalytic intramolecular PKR of chiral N-tethered 1,7-enynes [64].
Scheme 31: Model fluorinated alkynes used by Riera and Fustero [70].
Scheme 32: PKR with norbornadiene and fluorinated alkynes 58 [71].
Scheme 33: Nucleophilic addition/detrifluoromethylation and retro Diels-Alder reactions [70].
Scheme 34: Tentative mechanism for the nucleophilic addition/retro-aldol reaction sequence.
Scheme 35: Catalytic PKR with norbornadiene [70].
Scheme 36: Scope of the PKR of trifluoromethylalkynes with norbornadiene [72].
Scheme 37: DBU-mediated detrifluoromethylation [72].
Scheme 38: A simple route to enone 67, a common intermediate in the total synthesis of α-cuparenone.
Scheme 39: Effect of the olefin partner in the regioselectivity of the PKR with trifluoromethyl alkynes [79].
Scheme 40: Intermolecular PKR of trifluoromethylalkynes with 2-norbornene reported by the group of Konno [54].
Scheme 41: Intermolecular PKR of diarylalkynes with 2-norbornene reported by the group of Helaja [80].
Scheme 42: Intermolecular PKR reported by León and Fernández [81].
Scheme 43: PKR reported with cyclopropene 73 [82].
Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach
- Rhys A. Lippa,
- John A. Murphy and
- Tim N. Barrett
Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134
- occur via a radical pathway. When iodide 29 was replaced by a superior oxidant in 1,2-dibromoethane, formation of dimer 32 increased (17% isolated yield). This supports the previously reported proposals that dimerisation occurs via single-electron oxidation of the 2-picolyl anion by the halide
- /pseudohalide oxidant followed by recombination of the resulting picolyl radical [28][29][30]. Whilst trace oxygen may be involved, as indicated by the presence of alcohol 31, no dimerisation or alcohol formation was seen in the absence of a halide/pseudohalide-based oxidant, during C-phosphorylation or
Graphical Abstract
Figure 1: The Arg–Gly–Asp tripeptide sequence and examples of tetrahydro-1,8-naphthyridine-containing integri...
Scheme 1: Commonly used synthetic routes to tetrahydro-1,8-naphthyridine moieties by hydrogenation of saturat...
Scheme 2: Previous synthetic route to fluoropyrrolidine 6 utilising a Wittig reaction and the novel, higher y...
Scheme 3: Synthesis of phosphoramidate 9 from tetrahydro-1,8-naphthyridine 8. Conditions: s-BuLi (3 equiv), d...
Scheme 4: Mono- and diphosphorylation of tetrahydro-1,8-naphthyridine 11. Conditions: (i) s-BuLi (2 equiv), d...
Scheme 5: Synthesis of amine 6 from phosphonate 7 and aldehyde 5. Conditions: (i) T3P® (50% w/w in DCM, 3 equ...
Scheme 6: Monodeuteration of 13 as observed by 1H and 13C NMR. Conditions: s-BuLi (3 equiv), THF, −42 °C, 20 ...
Scheme 7: Sequential diphosphorylation of tetrahydronaphthyridine 11. Conditions: (i) iPrMgCl (1.5 equiv), TH...
Scheme 8: Possible mechanistic pathways for the formation of dimer 28. Conditions: KOt-Bu, THF, 1 h, 68% yiel...
Scheme 9: Alkylation of phosphoramidate 13 by iodide 29 to afford compound 30 and byproducts alcohol 31 and d...
Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita–Baylis–Hillman adducts
- Soundararajan Karthikeyan,
- Radha Krishnan Shobana,
- Kamarajapurathu Raju Subimol,
- J. Helen Ratna Monica and
- Ayyanoth Karthik Krishna Kumar
Beilstein J. Org. Chem. 2020, 16, 1579–1587, doi:10.3762/bjoc.16.130
- -lactams [6], quinolin-5-ones [7], spirobisglutarimides [8], indolizines [9], and spiro carbocyclic frameworks [10]. However, most of the reported synthetic transformations utilize either allylic hydroxy-protected or allyl halide-substituted MBH adducts [11][12][13][14][15][16][17][18][19][20][21][22][23
- transformations for complex molecules [29][30][31]. Two individual research groups have reported the multistep pathway to access the cinnamyl-1H-1,2,3-triazole derivatives IX from acetates of MBH adducts (Scheme 2) [32][33]. The other preferable moiety for triazole transformations is the allyl halide of MBH
Graphical Abstract
Scheme 1: Literature-reported cycloaddition reactions of MBH acetates involving azides and alkynes [24-28].
Scheme 2: Synthetic methodologies for triazolations of MBH adducts. a) Literature-reported indirect triazolat...
Scheme 3: Scope of the one-pot cascade reaction of the unprotected Morita–Baylis–Hillman adducts 3a–q.
Figure 1: Proposed mechanism for the synthesis of 1,4-disubstituted triazoles.
Scheme 4: Comparative analysis of the sequential one-pot reaction.
Figure 2: Proposed mechanism for the synthesis of 3-(bromomethyl)coumarins.
Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides
- Mateo Berton,
- Kevin Sheehan,
- Andrea Adamo and
- D. Tyler McQuade
Beilstein J. Org. Chem. 2020, 16, 1343–1356, doi:10.3762/bjoc.16.115
- optimization (Table S4, Supporting Information File 1), solubility issues hindered the formation of a concentrated solution (>0.8 M). The crystallization of iPrMgBr in the collection flask forced us to reduce the initial concentration of the organic halide to 0.9 M, yielding iPrMgBr (0.75 M, 82%, note: the
- yields reported herein refer to the amount of organometallic reagent produced in a steady state; no detectable halide was recovered, and the organometallic reagent purity was high unless otherwise stated, Table S4, entry 3, Supporting Information File 1). The reactivity order of organic halides against
- consistent results over a relatively large amount (≈100 mmol) of organic halide that was converted. We offer two explanations: (1) the higher purity of Mg chips (99.98%) and (2) the higher surface area (SA) of the Mg powder (≈130 mesh, SA ≈ 30 cm2/g) than Mg chips (≈20 mesh, SA ≈ 4 cm2/g). We hypothesize
Graphical Abstract
Figure 1: Comparing on-demand coffee and turbo Grignard pod-style machines.
Figure 2: Ranking of the 20 most cited Grignard reagents (SciFinder March 26, 2019).
Figure 3: On-demand prototype. A) Inside view of the pump with a flexible bag containing a yellow liquid layi...
Figure 4: Temperature evolution measured with thermocouples along the column outer surface at three different...
Figure 5: Stratified bicomponent column (Diba Omnifit EZ Solvent Plus) composed of magnesium (chips/powder, 1...
Scheme 1: Continuous flow synthesis of TMPMgCl⋅LiCl with a stratified packed-bed column of activated magnesiu...
Scheme 2: Continuous flow synthesis of TMPMgCl⋅LiBr with a stratified packed-bed column of activated magnesiu...
Scheme 3: Continuous flow synthesis of t-AmylOMgCl⋅LiCl with a stratified packed-bed column of activated magn...
Figure 6: Steady-state concentration stability during the conversion of iPrCl in THF (56 mL, 2.2 M) into iPrM...
Scheme 4: Synthesis of iPrMgCl⋅LiCl on the ODR prototype.
Scheme 5: Synthesis of HMDSMgCl⋅LiCl on the ODR prototype.
Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions
- Xiaoming Ma,
- Suzhi Meng,
- Xiaofeng Zhang,
- Qiang Zhang,
- Shenghu Yan,
- Yue Zhang and
- Wei Zhang
Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106
- IV which undergoes dissociation to afford product 9a. The hydridopalladium(II) halide is converted to the catalytically active Pd(0) with a base. Conclusion In summary, we have developed an efficient method through a three-component [3 + 2] cycloaddition followed by a one-pot N-allylation and an
Graphical Abstract
Figure 1: Bioactive pyrrolo[2,1-a]isoquinolines and hexahydropyrrolo[2,1-a]isoquinolines.
Scheme 1: [3 + 2] Cycloaddition with amino esters or amino acids.
Scheme 2: Scaffolds derived from the initial [3 + 2] adducts.
Scheme 3: [3 + 2] Cycloaddition with amino esters or amino acids. Conditions: 1:3:4 (1.2:1:1.1), Et3N (1.5 eq...
Scheme 4: Synthesis of pyrrolo[2,1-a]isoquinolines 9. Reaction conditions: 5 (0.5 mmol, 1 equiv), 7 (3 equiv)...
Scheme 5: Synthesis of pyrrolo[2,1-a]isoquinolines 11. Reaction conditions: 6 (0.5 mmol, 1 equiv), 7 (3 equiv...
Scheme 6: Synthesis of pyrrolo[2,1-a]isoquinolines 12. Reaction conditions: 5 or 6 (0.5 mmol, 1 equiv), cinna...
Scheme 7: Plausible mechanism for the synthesis of 9a.
Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis
- Stephanie G. E. Amos,
- Marion Garreau,
- Luca Buzzetti and
- Jerome Waser
Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103
- the nature of the halide: as a trend, aryl iodides are easier to reduce than aryl bromides and aryl chlorides [67][77]. Under organophotocatalytic conditions, the reduction can be achieved following two main strategies for accessing stronger reduction potentials: (a) tuning the electronics of the
Graphical Abstract
Figure 1: Selected examples of organic dyes. Mes-Acr+: 9-mesityl-10-methylacridinium, DCA: 9,10-dicyanoanthra...
Scheme 1: Activation modes in photocatalysis.
Scheme 2: Main strategies for the formation of C(sp3) radicals used in organophotocatalysis.
Scheme 3: Illustrative example for the photocatalytic oxidative generation of radicals from carboxylic acids:...
Scheme 4: Illustrative example for the photocatalytic reductive generation of C(sp3) radicals from redoxactiv...
Figure 2: Common substrates for the photocatalytic oxidative generation of C(sp3) radicals.
Scheme 5: Illustrative example for the photocatalytic oxidative generation of radicals from dihydropyridines ...
Scheme 6: Illustrative example for the photocatalytic oxidative generation of C(sp3) radicals from trifluorob...
Scheme 7: Illustrative example for the photocatalytic reductive generation of C(sp3) radicals from benzylic h...
Scheme 8: Illustrative example for the photocatalytic generation of C(sp3) radicals via direct HAT: the cross...
Scheme 9: Illustrative example for the photocatalytic generation of C(sp3) radicals via indirect HAT: the deu...
Scheme 10: Selected precursors for the generation of aryl radicals using organophotocatalysis.
Scheme 11: Illustrative example for the photocatalytic reductive generation of aryl radicals from aryl diazoni...
Scheme 12: Illustrative examples for the photocatalytic reductive generation of aryl radicals from haloarenes:...
Scheme 13: Illustrative example for the photocatalytic reductive generation of aryl radicals from aryl halides...
Scheme 14: Illustrative example for the photocatalytic reductive generation of aryl radicals from arylsulfonyl...
Scheme 15: Illustrative example for the reductive photocatalytic generation of aryl radicals from triaryl sulf...
Scheme 16: Main strategies towards acyl radicals used in organophotocatalysis.
Scheme 17: Illustrative example for the decarboxylative photocatalytic generation of acyl radicals from α-keto...
Scheme 18: Illustrative example for the oxidative photocatalytic generation of acyl radicals from acyl silanes...
Scheme 19: Illustrative example for the oxidative photocatalytic generation of carbamoyl radicals from 4-carba...
Scheme 20: Illustrative example of the photocatalytic HAT approach for the generation of acyl radicals from al...
Scheme 21: General reactivity of a) radical cations; b) radical anions; c) the main strategies towards aryl an...
Scheme 22: Illustrative example for the oxidative photocatalytic generation of alkene radical cations from alk...
Scheme 23: Illustrative example for the reductive photocatalytic generation of an alkene radical anion from al...
Figure 3: Structure of C–X radical anions and their neutral derivatives.
Scheme 24: Illustrative example for the photocatalytic reduction of imines and the generation of an α-amino C(...
Scheme 25: Illustrative example for the oxidative photocatalytic generation of aryl radical cations from arene...
Scheme 26: NCR classifications and generation.
Scheme 27: Illustrative example for the photocatalytic reductive generation of iminyl radicals from O-aryl oxi...
Scheme 28: Illustrative example for the photocatalytic oxidative generation of iminyl radicals from α-N-oxy ac...
Scheme 29: Illustrative example for the photocatalytic oxidative generation of iminyl radicals via an N–H bond...
Scheme 30: Illustrative example for the photocatalytic oxidative generation of amidyl radicals from Weinreb am...
Scheme 31: Illustrative example for the photocatalytic reductive generation of amidyl radicals from hydroxylam...
Scheme 32: Illustrative example for the photocatalytic reductive generation of amidyl radicals from N-aminopyr...
Scheme 33: Illustrative example for the photocatalytic oxidative generation of amidyl radicals from α-amido-ox...
Scheme 34: Illustrative example for the photocatalytic oxidative generation of aminium radicals: the N-aryltet...
Scheme 35: Illustrative example for the photocatalytic oxidative generation of nitrogen-centered radical catio...
Scheme 36: Illustrative example for the photocatalytic oxidative generation of nitrogen-centered radical catio...
Scheme 37: Illustrative example for the photocatalytic oxidative generation of hydrazonyl radical from hydrazo...
Scheme 38: Generation of O-radicals.
Scheme 39: Illustrative examples for the photocatalytic generation of O-radicals from N-alkoxypyridinium salts...
Scheme 40: Illustrative examples for the photocatalytic generation of O-radicals from alkyl hydroperoxides: th...
Scheme 41: Illustrative example for the oxidative photocatalytic generation of thiyl radicals from thiols: the...
Scheme 42: Main strategies and reagents for the generation of sulfonyl radicals used in organophotocatalysis.
Scheme 43: Illustrative example for the reductive photocatalytic generation of sulfonyl radicals from arylsulf...
Scheme 44: Illustrative example of a Cl atom abstraction strategy for the photocatalytic generation of sulfamo...
Scheme 45: Illustrative example for the oxidative photocatalytic generation of sulfonyl radicals from sulfinic...
Scheme 46: Illustrative example for the photocatalytic generation of electronically excited triplet states: th...
Scheme 47: Illustrative example for the photocatalytic generation of electronically excited triplet states: th...
Copper-based fluorinated reagents for the synthesis of CF2R-containing molecules (R ≠ F)
- Louise Ruyet and
- Tatiana Besset
Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92
- 87% yield) was investigated (Scheme 8) [52]. Finally, the Poisson’s group developed a methodology for the Ullman cross-coupling reaction between the in situ-generated CuCF2PO(OEt)2 and aryl iodides containing a coordinating group (e.g., CO2CH3, COCH3, NO2), at the ortho-position of the halide [52
Graphical Abstract
Scheme 1: Synthesis of the first isolable (NHC)CuCF2H complexes from TMSCF2H and their application for the sy...
Scheme 2: Pioneer works for the in situ generation of CuCF2H from TMSCF2H and from n-Bu3SnCF2H. Phen = 1,10-p...
Scheme 3: A Sandmeyer-type difluoromethylation reaction via the in situ generation of CuCF2H from TMSCF2H. a ...
Scheme 4: A one pot, two-step sequence for the difluoromethylthiolation of various classes of compounds via t...
Scheme 5: A copper-mediated oxidative difluoromethylation of terminal alkynes via the in situ generation of a...
Scheme 6: A copper-mediated oxidative difluoromethylation of heteroarenes.
Scheme 7: Synthesis of difluoromethylphosphonate-containing molecules using the in situ-generated CuCF2PO(OEt)...
Scheme 8: Synthesis of difluoromethylphosphonate-containing molecules using in situ-generated CuCF2PO(OEt)2 s...
Scheme 9: Synthesis of difluoromethylphosphonate-containing molecules using in situ-generated CuCF2PO(OEt)2 s...
Scheme 10: Synthesis of (diethylphosphono)difluoromethylthiolated molecules using in situ-generated CuCF2PO(OE...
Scheme 11: Access to (diethylphosphono)difluoromethylthiolated molecules via the in situ generation of CuCF2PO...
Scheme 12: Synthesis of (phenylsulfonyl)difluoromethyl-containing molecules via the in situ generation of CuCF2...
Scheme 13: Copper-mediated 1,1-difluoroethylation of diaryliodonium salts by using the in situ-generated CuCF2...
Scheme 14: Pioneer works for the pentafluoroethylation and heptafluoropropylation using a copper-based reagent...
Scheme 15: Pentafluoroethylation of (hetero)aryl bromides using the (Phen)CuCF2CF3 complex. 19F NMR yields wer...
Scheme 16: Synthesis of pentafluoroethyl ketones using the (Ph3P)Cu(phen)CF2CF3 reagent. 19F NMR yields were g...
Scheme 17: Synthesis of (Phen)2Cu(O2CCF2RF) and functionalization of (hetero)aryl iodides.
Scheme 18: Pentafluoroethylation of arylboronic acids and (hetero)aryl bromides via the in situ-generated CuCF2...
Scheme 19: In situ generation of CuCF2CF3 species from a cyclic-protected hexafluoroacetone and KCu(Ot-Bu)2. 19...
Scheme 20: Pentafluoroethylation of bromo- and iodoalkenes. Only examples of isolated compounds were depicted.
Scheme 21: Fluoroalkylation of aryl halides via a RCF2CF2Cu species.
Scheme 22: Synthesis of perfluoroorganolithium copper species or perfluroalkylcopper derivatives from iodoperf...
Scheme 23: Formation of the PhenCuCF2CF3 reagent by means of TFE and pentafluoroethylation of iodoarenes and a...
Scheme 24: Generation of a CuCF2CF3 reagent from TMSCF3 and applications.
Fluorinated phenylalanines: synthesis and pharmaceutical applications
- Laila F. Awad and
- Mohammed Salah Ayoup
Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91
- reported herein different methods for their synthesis. 1.1. Negishi cross coupling of aryl halide and organozinc compounds Jackson and co-workers reported the synthesis of a range of phenylalanine derivatives via Negishi cross-coupling reactions of aryl halides and Zn homoenolates of the protected (R
- involved a Negishi cross coupling of an aryl halide and the Zn homoenolate of the protected (R)-iodoalanine 2 using a Pd(0) catalyst. This method provided a versatile range of fluorinated phenylalanine products with high enantioselectivities and in acceptable yields. 2. Synthesis of β-fluorophenylalanines
Graphical Abstract
Figure 1: Categories I–V of fluorinated phenylalanines.
Scheme 1: Synthesis of fluorinated phenylalanines via Jackson’s method.
Scheme 2: Synthesis of all-cis-tetrafluorocyclohexylphenylalanines.
Scheme 3: Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine (nPt: neopentyl, TCE: trichloroethyl).
Scheme 4: Synthesis of ʟ-4-[sulfono(difluoromethyl)]phenylalanine derivatives 17.
Scheme 5: Synthesis of fluorinated Phe analogues from Cbz-protected aminomalonates.
Scheme 6: Synthesis of tetrafluorophenylalanine analogues via the 3-methyl-4-imidazolidinone auxiliary 25.
Scheme 7: Synthesis of tetrafluoro-Phe derivatives via chiral auxiliary 31.
Scheme 8: Synthesis of 2,5-difluoro-Phe and 2,4,5-trifluoro-Phe via Schöllkopf reagent 34.
Scheme 9: Synthesis of 2-fluoro- and 2,6-difluoro Fmoc-Phe derivatives starting from chiral auxiliary 39.
Scheme 10: Synthesis of 2-[18F]FPhe via chiral auxiliary 43.
Scheme 11: Synthesis of FPhe 49a via photooxidative cyanation.
Scheme 12: Synthesis of FPhe derivatives via Erlenmeyer azalactone synthesis.
Scheme 13: Synthesis of (R)- and (S)-2,5-difluoro Phe via the azalactone method.
Scheme 14: Synthesis of 3-bromo-4-fluoro-(S)-Phe (65).
Scheme 15: Synthesis of [18F]FPhe via radiofluorination of phenylalanine with [18F]F2 or [18F]AcOF.
Scheme 16: Synthesis of 4-borono-2-[18F]FPhe.
Scheme 17: Synthesis of protected 4-[18F]FPhe via arylstannane derivatives.
Scheme 18: Synthesis of FPhe derivatives via intermediate imine formation.
Scheme 19: Synthesis of FPhe derivatives via Knoevenagel condensation.
Scheme 20: Synthesis of FPhe derivatives 88a,b from aspartic acid derivatives.
Scheme 21: Synthesis of 2-(2-fluoroethyl)phenylalanine derivatives 93 and 95.
Scheme 22: Synthesis of FPhe derivatives via Zn2+ complexes.
Scheme 23: Synthesis of FPhe derivatives via Ni2+ complexes.
Scheme 24: Synthesis of 3,4,5-trifluorophenylalanine hydrochloride (109).
Scheme 25: Synthesis of FPhe derivatives via phenylalanine aminomutase (PAM).
Scheme 26: Synthesis of (R)-2,5-difluorophenylalanine 115.
Scheme 27: Synthesis of β-fluorophenylalanine via 2-amino-1,3-diol derivatives.
Scheme 28: Synthesis of β-fluorophenylalanine derivatives via the oxazolidinone chiral auxiliary 122.
Scheme 29: Synthesis of β-fluorophenylalanine from pyruvate hemiketal 130.
Scheme 30: Synthesis of β-fluorophenylalanine (136) via fluorination of β-hydroxyphenylalanine (137).
Scheme 31: Synthesis of β-fluorophenylalanine from aziridine derivatives.
Scheme 32: Synthesis of β-fluorophenylalanine 136 via direct fluorination of pyruvate esters.
Scheme 33: Synthesis of β-fluorophenylalanine via fluorination of ethyl 3-phenylpyruvate enol using DAST.
Scheme 34: Synthesis of β-fluorophenylalanine derivatives using photosensitizer TCB.
Scheme 35: Synthesis of β-fluorophenylalanine derivatives using Selectflour and dibenzosuberenone.
Scheme 36: Synthesis of protected β-fluorophenylalanine via aziridinium intermediate 150.
Scheme 37: Synthesis of β-fluorophenylalanine derivatives via fluorination of α-hydroxy-β-aminophenylalanine d...
Scheme 38: Synthesis of β-fluorophenylalanine derivatives from α- or β-hydroxy esters 152a and 155.
Scheme 39: Synthesis of a series of β-fluoro-Phe derivatives via Pd-catalyzed direct fluorination of β-methyle...
Scheme 40: Synthesis of series of β-fluorinated Phe derivatives using quinoline-based ligand 162 in the Pd-cat...
Scheme 41: Synthesis of β,β-difluorophenylalanine derivatives from 2,2-difluoroacetaldehyde derivatives 164a,b....
Scheme 42: Synthesis of β,β-difluorophenylalanine derivatives via an imine chiral auxiliary.
Scheme 43: Synthesis of α-fluorophenylalanine derivatives via direct fluorination of protected Phe 174.
Figure 2: Structures of PET radiotracers of 18FPhe derivatives.
Figure 3: Structures of melfufen (179) and melphalan (180) anticancer drugs.
Figure 4: Structure of gastrazole (JB95008, 181), a CCK2 receptor antagonist.
Figure 5: Dual CCK1/CCK2 antagonist 182.
Figure 6: Structure of sitagliptin (183), an antidiabetic drug.
Figure 7: Structure of retaglpitin (184) and antidiabetic drug.
Figure 8: Structure of evogliptin (185), an antidiabetic drug.
Figure 9: Structure of LY2497282 (186) a DPP-4 inhibitor for the treatment of type II diabetes.
Figure 10: Structure of ulimorelin (187).
Figure 11: Structure of GLP1R (188).
Figure 12: Structures of Nav1.7 blockers 189 and 190.
Recent advances in Cu-catalyzed C(sp3)–Si and C(sp3)–B bond formation
- Balaram S. Takale,
- Ruchita R. Thakore,
- Elham Etemadi-Davan and
- Bruce H. Lipshutz
Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67
Graphical Abstract
Scheme 1: Pharmaceuticals possessing a silicon or boron atom.
Scheme 2: The first Cu-catalyzed C(sp3)–Si bond formation.
Scheme 3: Conversion of benzylic phosphate 6 to the corresponding silane.
Scheme 4: Conversion of alkyl triflates to alkylsilanes.
Scheme 5: Conversion of secondary alkyl triflates to alkylsilanes.
Scheme 6: Conversion of alkyl iodides to alkylsilanes.
Scheme 7: Trapping of intermediate radical through cascade reaction.
Scheme 8: Radical pathway for conversion of alkyl iodides to alkylsilanes.
Scheme 9: Conversion of alkyl ester of N-hydroxyphthalimide to alkylsilanes.
Scheme 10: Conversion of gem-dibromides to bis-silylalkanes.
Scheme 11: Conversion of imines to α-silylated amines (A) and the reaction pathway (B).
Scheme 12: Conversion of N-tosylimines to α-silylated amines.
Scheme 13: Screening of diamine ligands.
Scheme 14: Conversion of N-tert-butylsulfonylimines to α-silylated amines.
Scheme 15: Conversion of aldimines to nonracemic α-silylated amines.
Scheme 16: Conversion of N-tosylimines to α-silylated amines.
Scheme 17: Reaction pathway [A] and conversion of aldehydes to α-silylated alcohols [B].
Scheme 18: Conversion of aldehydes to benzhydryl silyl ethers.
Scheme 19: Conversion of ketones to 1,2-diols (A) and conversion of imines to 1,2-amino alcohols (B).
Scheme 20: Ligand screening (A) and conversion of aldehydes to α-silylated alcohols (B).
Scheme 21: Conversion of aldehydes to α-silylated alcohols.
Scheme 22: 1,4-Additions to α,β-unsaturated ketones.
Scheme 23: 1,4-Additions to unsaturated ketones to give β-silylated derivatives.
Scheme 24: Additions onto α,β-unsaturated lactones to give β-silylated lactones.
Scheme 25: Conversion of α,β-unsaturated to β-silylated lactams.
Scheme 26: Conversion of N-arylacrylamides to silylated oxindoles.
Scheme 27: Conversion of α,β-unsaturated carbonyl compounds to silylated tert-butylperoxides.
Scheme 28: Catalytic cycle for Cu(I) catalyzed α,β-unsaturated compounds.
Scheme 29: Conversion of p-quinone methides to benzylic silanes.
Scheme 30: Conversion of α,β-unsaturated ketimines to regio- and stereocontrolled allylic silanes.
Scheme 31: Conversion of α,β-unsaturated ketimines to enantioenriched allylic silanes.
Scheme 32: Regioselective conversion of dienedioates to allylic silanes.
Scheme 33: Conversion of alkenyl-substituted azaarenes to β-silylated adducts.
Scheme 34: Conversion of conjugated benzoxazoles to enantioenriched β-silylated adducts.
Scheme 35: Conversion of α,β-unsaturated carbonyl indoles to α-silylated N-alkylated indoles.
Scheme 36: Conversion of β-amidoacrylates to α-aminosilanes.
Scheme 37: Conversion of α,β-unsaturated ketones to enantioenriched β-silylated ketones, nitriles, and nitro d...
Scheme 38: Regio-divergent silacarboxylation of allenes.
Scheme 39: Silylation of diazocarbonyl compounds, (A) asymmetric and (B) racemic.
Scheme 40: Enantioselective hydrosilylation of alkenes.
Scheme 41: Conversion of 3-acylindoles to indolino-silanes.
Scheme 42: Proposed mechanism for the silylation of 3-acylindoles.
Scheme 43: Silyation of N-chlorosulfonamides.
Scheme 44: Conversion of acyl silanes to α-silyl alcohols.
Scheme 45: Conversion of N-tosylaziridines to β-silylated N-tosylamines.
Scheme 46: Conversion of N-tosylaziridines to silylated N-tosylamines.
Scheme 47: Conversion of 3,3-disubstituted cyclopropenes to silylated cyclopropanes.
Scheme 48: Conversion of conjugated enynes to 1,3-bis(silyl)propenes.
Scheme 49: Proposed sequence for the Cu-catalyzed borylation of substituted alkenes.
Scheme 50: Cu-catalyzed synthesis of nonracemic allylic boronates.
Scheme 51: Cu–NHC catalyzed synthesis of α-substituted allylboronates.
Scheme 52: Synthesis of α-chiral (γ-alkoxyallyl)boronates.
Scheme 53: Cu-mediated formation of nonracemic cis- or trans- 2-substituted cyclopropylboronates.
Scheme 54: Cu-catalyzed synthesis of γ,γ-gem-difluoroallylboronates.
Scheme 55: Cu-catalyzed hydrofunctionalization of internal alkenes and vinylarenes.
Scheme 56: Cu-catalyzed Markovnikov and anti-Markovnikov borylation of alkenes.
Scheme 57: Cu-catalyzed borylation/ortho-cyanation/Cope rearrangement.
Scheme 58: Borylfluoromethylation of alkenes.
Scheme 59: Cu-catalyzed synthesis of tertiary nonracemic alcohols.
Scheme 60: Synthesis of densely functionalized and synthetically versatile 1,2- or 4,3-borocyanated 1,3-butadi...
Scheme 61: Cu-catalyzed trifunctionalization of allenes.
Scheme 62: Cu-catalyzed selective arylborylation of arenes.
Scheme 63: Asymmetric borylative coupling between styrenes and imines.
Scheme 64: Regio-divergent aminoboration of unactivated terminal alkenes.
Scheme 65: Cu-catalyzed 1,4-borylation of α,β-unsaturated ketones.
Scheme 66: Cu-catalyzed protodeboronation of α,β-unsaturated ketones.
Scheme 67: Cu-catalyzed β-borylation of α,β-unsaturated imines.
Scheme 68: Cu-catalyzed synthesis of β-trifluoroborato carbonyl compounds.
Scheme 69: Asymmetric 1,4-borylation of α,β-unsaturated carbonyl compounds.
Scheme 70: Cu-catalyzed ACB and ACA reactions of α,β-unsaturated 2-acyl-N-methylimidazoles.
Scheme 71: Cu-catalyzed diborylation of aldehydes.
Scheme 72: Umpolung pathway for chiral, nonracemic tertiary alcohol synthesis (top) and proposed mechanism for...
Scheme 73: Cu-catalyzed synthesis of α-hydroxyboronates.
Scheme 74: Cu-catalyzed borylation of ketones.
Scheme 75: Cu-catalyzed borylation of unactivated alkyl halides.
Scheme 76: Cu-catalyzed borylation of allylic difluorides.
Scheme 77: Cu-catalyzed borylation of cyclic and acyclic alkyl halides.
Scheme 78: Cu-catalyzed borylation of unactivated alkyl chlorides and bromides.
Scheme 79: Cu-catalyzed decarboxylative borylation of carboxylic acids.
Scheme 80: Cu-catalyzed borylation of benzylic, allylic, and propargylic alcohols.
Rhodium-catalyzed reductive carbonylation of aryl iodides to arylaldehydes with syngas
- Zhenghui Liu,
- Peng Wang,
- Zhenzhong Yan,
- Suqing Chen,
- Dongkun Yu,
- Xinhui Zhao and
- Tiancheng Mu
Beilstein J. Org. Chem. 2020, 16, 645–656, doi:10.3762/bjoc.16.61
- no substituent group provided benzaldehyde (1) with 93% yield. For iodobenzene derivatives with electron-donating groups (Me, OMe), 83–95% yield of aldehydes 2–7 were obtained. As expected, the yields increased in the order of ortho < meta < para-substituted compounds. As for aryl iodides with halide
- . Afterwards, the hot mixture was filtered. Finally, the solid was washed with ether and dried under vacuum overnight to afford RhCl(PPh3)3 as maroon powder. The preparations of RhBr(PPh3)3 and RhI(PPh3)3 were similar only with different halide ions. Rhodium-catalyzed reductive carbonylation of iodobenzene
Graphical Abstract
Figure 1: Rhodium-catalyzed reductive carbonylation of iodobenzene with CO and H2 to afford benzaldehyde. a) ...
Scheme 1: Scaled-up experiment of the reductive carbonylation of iodobenzene to benzaldehyde under the optimi...
Scheme 2: Catalytic species participating in the catalytic process.
Scheme 3: Substrate scope for the Rh-catalyzed reductive carbonylation of aryl iodides using CO and H2. React...
Scheme 4: Isotope-labeling experiments.
Scheme 5: Proposed reaction mechanism for the Rh-catalyzed reductive carbonylation of aryl iodides using CO a...
Copper-catalyzed O-alkenylation of phosphonates
- Nuria Vázquez-Galiñanes,
- Mariña Andón-Rodríguez,
- Patricia Gómez-Roibás and
- Martín Fañanás-Mastral
Beilstein J. Org. Chem. 2020, 16, 611–615, doi:10.3762/bjoc.16.56
- all cases the corresponding enol phosphonates 3a–d in good yields. Importantly, no double alkenylation product was observed in any case. Benzyl and alkyl diethyl phosphonates bearing halide groups also worked well and led to enol phosphonates 3e and 3f in good yields without any traces of side
Graphical Abstract
Scheme 1: Synthesis of mixed alkyl alkenyl phosphonates.
Scheme 2: Scope of the copper-catalyzed alkenylation of dialkyl phosphonates. Reactions run on a 0.2 mmol sca...
