Organocatalysis
Organocatalysis describes catalysis with low-molecular-weight organic compounds, in which a metal is not part of the active principle. Organocatalysts donate or remove electrons or protons as their activation mode. There are additional aspects that belong to the field and that are being actively researched, including supported catalysts, organocatalysis in unusual reaction media, and applications in polymerizations, in total synthesis and drug-discovery, as well as in drug manufacturing, among many others. Certain things that cannot be done with enzymes or metals may well be feasible with organic catalysts.
See also the Thematic Series:
Transition-metal and organocatalysis in natural product synthesis
Sustainable catalysis
- Full Research Paper
- Published 16 Apr 2012
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Figure 1: Biologically active natural products and drugs containing the piperidine ring.
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Scheme 1: A general strategy to 5-nitropiperidin-2-ones and related heterocycles.
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Scheme 2: The synthesis of Michael adduct model substrates for the nitro-Mannich/lactamisation cascade.
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Scheme 3: Nitro-Mannich/lactamisation cascade with in situ formed imines.
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Figure 2: Cyclic imines employed in nitro-Mannich/lactamisation cascade.
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Scheme 4: Nitro-Mannich/lactamisation cascade of diastereomeric Michael adducts 6a, 6a’’ with cyclic imine 5a....
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Scheme 5: Nitro-Mannich/lactamisation cascade with cyclic imines. aDiastereomeric ratio in a crude reaction m...
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Scheme 6: Possible explanations for the observed high stereoselectivities in the nitro-Mannich/lactamisation ...
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Scheme 7: Thermodynamically-driven epimerisation of 5-nitropiperidin-2-ones 2m and 2m’.
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Figure 3: Thermodynamically driven epimerisation of 5-nitropiperidin-2-ones 2m and 2m’; identical diastereome...
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Scheme 8: One-pot three/four-component enantioselective Michael addition/nitro-Mannich/lactamisation cascade.
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Scheme 9: Protodenitration of 5-nitropiperidin-2-ones.
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Scheme 10: Various reductions of denitrated heterocycles.
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- Letter
- Published 27 Apr 2012
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Scheme 1: Plausible mechanism for Tf2NH-catalyzed isomerization of silyl enol ethers.
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Scheme 2: Regioselective formation of bicyclo[4.2.0]octanes from the same substrates by the isomerization–(2 ...
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Scheme 3: Formation of bicyclo[5.2.0]octane from the regioisomeric mixture of silyl enol ethers.
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- Letter
- Published 07 May 2012
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Figure 1: Structures of chiral organocatalysts.
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- Letter
- Published 16 Jul 2012
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Scheme 1: Paths to the formation of 1,3-dipolar synthons by using a catalytic amount of phosphines.
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Figure 1: The ORTEP plot of compound 3r.
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Figure 2: 31P NMR spectra (161.9 MHz, CDCl3) of control experiments.
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Scheme 2: Proposed transition models.
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Scheme 3: Dihydroxylation of 3c.
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- Published 18 Jul 2012
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Figure 1: Furocoumarins.
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Scheme 1: Synthesis of smyrindiol (1) by Grande et al.
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Scheme 2: Synthesis of smyrindiol by Snider et al.
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Scheme 3: Proline-catalyzed intramolecular aldol reaction of O-acetonyl-salicylaldehydes.
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Scheme 4: First retrosynthetic analysis.
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Scheme 5: Attempted proline catalyzed aldol reaction.
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Scheme 6: Second retrosynthetic analysis.
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Scheme 7: Asymmetric total synthesis of smyrindiol (1).
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- Published 03 Aug 2012
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Figure 1: Biologically interesting α-fluorinated β-ketoesters.
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Scheme 1: Preparation of quinine ester C-1.
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Figure 2: Promoters for asymmetric fluorination.
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Scheme 2: Preparation of 2a by using recycled quinine ester C-1.
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Figure 3: The asymmetric fluorination of various β-ketoesters.
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- Letter
- Published 06 Aug 2012
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Scheme 1: Allylic amination of MBH carbonates of isatins to access 3-amino-2-oxindoles.
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Scheme 2: Synthetic transformations of multifunctional product 4d.
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- Letter
- Published 13 Aug 2012
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Scheme 1: Working hypothesis: Decarboxylative Mannich reaction.
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- Letter
- Published 17 Aug 2012
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Figure 1: Oxygen-functionalized indole compounds.
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Figure 2: Resin-supported peptide catalyst.
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Scheme 1: Effect of the stereostructure of the peptide catalyst.
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- Letter
- Published 23 Aug 2012
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Figure 1: Cinchona alkaloid-derived catalysts screened for condition optimization (Table 1).
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Scheme 1: A one-pot synthesis of enantioenriched 3,3-diaryloxindoles.
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- Review
- Published 27 Aug 2012
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Scheme 1: Triflic acid-catalysed synthesis of cyclic aminals.
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Scheme 2: PTSA-catalysed synthesis of cyclic aminals.
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Scheme 3: Plausible mechanism for cyclic aminal synthesis.
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Scheme 4: Annulation cascade reaction with double nucleophiles.
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Scheme 5: Mechanism for the indole-annulation cascade reaction.
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Scheme 6: Synthesis of N-alkylpyrroles and δ-hydroxypyrroles.
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Scheme 7: Synthesis of N-alkylindoles 9 and N-alkylindolines 10.
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Scheme 8: Mechanistic study for the N-alkylpyrrole formation.
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Scheme 9: Benzoic acid catalysed decarboxylative redox amination.
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Scheme 10: Organocatalytic redox reaction of ortho-(dialkylamino)cinnamaldehydes.
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Scheme 11: Mechanism for aminocatalytic redox reaction of ortho-(dialkylamino)cinnamaldehydes.
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Scheme 12: Asymmetric synthesis of tetrahydroquinolines having gem-methyl ester groups.
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Scheme 13: Asymmetric synthesis of tetrahydroquinolines from chiral substrates 18.
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Scheme 14: Organocatalytic biaryl synthesis by Kwong, Lei and co-workers.
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Scheme 15: Organocatalytic biaryl synthesis by Shi and co-workers.
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Scheme 16: Organocatalytic biaryl synthesis by Hayashi and co-workers.
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Scheme 17: Proposed mechanism for organocatalytic biaryl synthesis.
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Highly enantioselective access to cannabinoid-type tricyles by organocatalytic Diels–Alder reactions
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- Published 28 Aug 2012
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Figure 1: An assortment of natural products synthesized by Diels–Alder reactions.
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Figure 2: Intermediates towards the total synthesis of (−)-Δ9-tetrahydrocannabinol (4).
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Scheme 1: Synthesis of thiourea catalysts 9a–l.
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Scheme 2: Organocatalytic Diels–Alder reaction with thiourea-catalysis.
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Figure 3: Formation of the iminium-ion.
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Scheme 3: Synthesis of electron poor imidazolidinone catalysts.
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Figure 4: Crystal structure of the side product from the reaction of 13.
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Figure 5: Confirmation of the relative configuration with NOESY experiments and X-ray crystal structures of t...
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Scheme 4: Co-catalyst screening.
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Scheme 5: Screening of imidazolidinone catalysts 15.
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- Published 31 Aug 2012
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Scheme 1: Reactions for the methyl cation affinity (MCA) of a neutral Lewis base (1a), an anionic Lewis base ...
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Figure 1: MCA values of monosubstituted amines of general formula Me2N(CH2)nH (n = 1–7, in kJ/mol).
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Scheme 2: Systematic dependence of MCA.
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Scheme 3: Trends in amine MCA values.
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Figure 2: Eclipsing interactions in the best conformation of N+Me(iPr)3 (16Me) (left), and the corresponding ...
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Scheme 4: General expression for the chain-length dependence of MCA values.
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Figure 3: MCA values of monosubstituted phosphanes of general formula Me2P(CH2)nH (n = 1–8, in kJ/mol).
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Figure 4: MCA values of monosubstituted phosphanes of general formula PMe2(CH(CH2)n+1) (n = 1–8, in kJ/mol).
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Figure 5: The MCA values of n-butyldiphenylphosphane (102) and its (αα-/ββ-/γγ-) dimethylated analogues.
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Figure 6: MCA values of phosphanes Me2P–NR2 with cyclic and acyclic amine substituents.
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Figure 7: MCA values of phosphanes PMe2R connected to α,α- and β,β-position of nitrogen containing cyclic sub...
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Scheme 5: Reactions for the benzhydryl cation affinity (BHCA) of a Lewis base (5a) and pyridine (5b).
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Figure 8: Comparison of BHCA values (kJ/mol) and nucleophilicity parameters N for sterically unbiased pyridin...
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Scheme 6: Reactions for the trityl cation affinity (THCA) of a Lewis base (6a) and pyridine (6b).
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Figure 9: Comparison of MCA, BHCA, and TCA values of selected Lewis bases.
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Scheme 7: Correlations of BHCA/TCA values with the respective MCA data for sterically unbiased systems (exclu...
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Figure 10: Scheme for the angle d(RXRR) measurements.
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Scheme 8: Reactions for the Mosher's cation affinity (MOSCA) of a Lewis base.
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Scheme 9: Reactions for the acetyl cation affinity (ACA) of a Lewis base (9a) and pyridine (9b).
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Figure 11: Structure of the acetylated pyridine 380 (380Ac).
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Scheme 10: Reaction for the Michael-acceptor affinity (MAA) of a Lewis base.
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Figure 12: Inverted reaction free energies for the addition of N- and P-based Lewis bases to three different M...
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Figure 13: Correlation between MCA values and affinity values towards three different Michael acceptors.
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Scheme 11: (a) General definition for a methyl cation transfer reaction between Lewis bases LB1 and LB2, and (...
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Figure 14: The energetically best conformations of Pn-Bu3 (120_1, top) and (120_2, bottom).
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Figure 15: Relative order of the conformations 120_1 to 120_7 depending on the level of theory.
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Figure 16: The structure of the energetically best conformations of 120Me.
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- Published 03 Sep 2012
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Figure 1: General structure of sulfoximines 1 and one of the enantiomers of S-methyl-S-phenylsulfoximine ((S)-...
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Figure 2: Structures of chiral mono- and bifunctional (bis-)thioureas that have been used as organocatalysts.
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Scheme 1: Synthesis of compound (S)-3.
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Scheme 2: Organocatalytic desymmetrization of the cyclic anhydride 4 with (S)-3.
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Scheme 3: Attempted synthesis of sulfonimidoyl-substituted thiourea (R)-9.
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Scheme 4: Synthesis of the sulfonimidoyl-containing thioureas (S)-12 and (S)-13.
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Scheme 5: Syntheses of ethylene-linked sulfonimidoyl-containing thioureas (SS,SC)-18 and (RS,SC)-19.
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- Published 04 Sep 2012
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Figure 1: The conjugated addition to unsaturated 1,4-diketone 1.
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Figure 2: Organocatalysts screened.
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Figure 3: Proposed transition state.
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Figure 4: Calculated (red) and experimental (blue) IR (A) and VCD spectrum (B) of compound (R)-3a.
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- Published 05 Sep 2012
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Figure 1: Second-order rate constants for reactions of electrophiles with nucleophiles.
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Figure 2: Mechanism of amine-catalyzed conjugate additions of nucleophiles [23-28].
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Figure 3: Kinetics of the reactions of the iminium ion 3a with the silylated ketene acetal 7a [35].
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Figure 4: Laser flash photolytic generation of iminium ions 3a.
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Figure 5: Correlations of the reactivities of the iminium ions 3a and 3b toward nucleophiles with the corresp...
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Figure 6: Comparison of the electrophilicities of cinnamaldehyde-derived iminium ions 3a–3i.
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Figure 7: Nucleophiles used in iminium activated reactions [35,42,44-52].
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Figure 8: Counterion effects in electrophilic reactions of iminium ions 3a-X (at 20 °C, silyl ketene acetal 7b...
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Figure 9: Comparison of calculated and experimental rate constants of electrophilic aromatic substitutions wi...
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Figure 10: Aza-Michael additions of the imidazoles 15 with the iminium ion 3a [58].
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Figure 11: Plots of log k2 for the reactions of enamides 17a–17e with the benzhydrylium ions 18a–d in CH3CN at...
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Figure 12: Comparison of the nucleophilicities of enamides 17 with those of several other C nucleophiles (solv...
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Figure 13: Experimental and calculated rate constants k2 for the reactions of 17b and 17g with 3a and 3b in th...
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Figure 14: Comparison between experimental and calculated (Equation 1) cyclopropanation rate constants [64].
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Figure 15: Electrostatic activation of iminium activated cyclopropanations with sulfur ylides.
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Figure 16: Sulfur ylides inhibit the formation of iminium ions.
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Figure 17: Enamine activation [65].
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Figure 18: Electrophilicity parameters E for classes of compounds that have been used as electrophilic substra...
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Figure 19: Quantification of the nucleophilic reactivities of the enamines 32a–e in acetonitrile (20 °C) [83]; a d...
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Figure 20: Proposed transition states for the stereogenic step in proline-catalyzed reactions.
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Figure 21: Kinetic evidence for the anchimeric assistance of the electrophilic attack by the carboxylate group....
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Figure 22: Differentiation of nucleophilicity and Lewis basicity (in acetonitrile at 20 °C): Rate (left) and e...
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Figure 23: NHCs 41, 42, and 43 are moderately active nucleophiles and exceptionally strong Lewis bases (methyl...
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Figure 24: Nucleophilic reactivities of the deoxy Breslow intermediates 45 in THF at 20 °C [107].
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Figure 25: Comparison of the proton affinities (PA, from [107]) of the diaminoethylenes 47a–c with the methyl catio...
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Figure 26: Berkessel’s synthesis of a Breslow intermediate (51, keto tautomer) from carbene 43 [112].
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Figure 27: Synthesis of O-methylated Breslow intermediates [114].
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Figure 28: Relative reactivities of deoxy- and O-methylated Breslow intermediates [114].
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Figure 29: Reactivity scales for electrophiles and nucleophiles relevant for organocatalytic reactions (refere...
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- Published 07 Sep 2012
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Scheme 1: Synthesis of guanidine-thiourea organocatalyst 7.
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Scheme 2: Henry reaction of 3-phenylpropionaldehyde (8) with nitromethane (9).
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Scheme 3: Michael addition of (12) and (14) to trans-β-nitrostyrene (11).
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Figure 1: Optimized geometries of four conformers of catalyst 7. Energies are in kcal·mol−1, B3PW91/6–31G(d) ...
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Scheme 4: Energy profile for the first step of the reaction between catalyst 7 and malonate 14. Energies are ...
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Figure 2: Complexes (CatN1–CatN5) between catalyst 7 and nitrostyrene 11. Energies are in kcal·mol−1, B3PW91/...
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Scheme 5: Two possible routes for ternary complex formation. Energies are in kcal·mol−1, B3PW91/6–31G(d) (fir...
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Figure 3: Geometries of transition states for R and S products. Relative energies (with respect to Init10) ar...
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Figure 4: Geometries of transition states for R and S products. Relative energies (with respect to Init10) ar...
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Figure 5: B3PW91/6–31G(d) (first entry), DFT-PCM (second entry), MP2/6–31G(d)//B3PW91/6–31G(d) (third entry) ...
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Figure 6: Geometries of transition states for R and S products with 7-TABD catalyst. Relative energies (to In...
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- Published 10 Sep 2012
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Figure 1: Synthetic methods for α-amino-β-keto esters.
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Figure 2: Structures of several NHC precatalysts.
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Scheme 1: Scope of aliphatic aldehydes.
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Scheme 2: Cross-over experiments.
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Scheme 3: Proposed reaction mechanism.
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- Published 26 Sep 2012
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Scheme 1: Conditions for the cyclization of 2’-hydroxycinnamate and related precursors to coumarins. (a) Ther...
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Scheme 2: Hypothetical catalytic cycle: Nucleophile-assisted cyclization of (E)-ethyl 2’-hydroxycinnamate (1)...
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Scheme 3: Proposed catalytic cycle, based on 31P NMR spectroscopic and color evidence.
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- Published 09 Oct 2012
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Figure 1: Important heterocycles containing pyrazolidine or pyrazoline structures.
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Figure 2: X-ray crystal structure of racemic 4a (25% thermal ellipsoids).
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Figure 3: X-ray crystal structure of racemic 4n (25% thermal ellipsoids).
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Figure 4: The X-ray crystal structure of chiral compound 4s (40% thermal ellipsoids).
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- Published 12 Oct 2012
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Scheme 1: Regioselective ring opening of an aziridine-2-carboxylate.
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Figure 1: Amine-promoted alkene aziridination.
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Figure 2: Ring-opened products of aziridine 1a.
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- Published 17 Oct 2012
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Figure 1: Chiral PPY catalysts.
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Scheme 1: Asymmetric desymmetrization of 5 with catalyst 3.
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Scheme 2: Preparation of a small library of chiral C2-symmetric PPY catalysts (reference, see [12]).
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Scheme 3: Amplification of enantiomeric purity of the major enantiomer produced at the step of asymmetric des...
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Scheme 4: Acylative kinetic resolution of racemic-6 with catalyst 12b.
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Figure 2: A hypothetical model for the transition-state assembly of the asymmetric acylation of 5 promoted by...
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Figure 3: An alternative model for the transition state assembly of the asymmetric acylation of 5 promoted by...
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- Published 18 Oct 2012
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Scheme 1: Diels–Alder reaction with ethyl crotonthioate (1) and cyclopentadiene (2).
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Scheme 2: Diels–Alder reaction catalysed with imidazolinium salts.
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Scheme 3: Ring opening of thiirane 12.
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Scheme 4: Ring opening of epoxide 14.
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Scheme 5: Synthesis of bis-imidazolium salt 17.
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Scheme 6: Synthesis of amidinium salt 21.
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- Published 23 Oct 2012
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Scheme 1: Brønsted acid catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene.
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- Published 06 Dec 2012
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Scheme 1: Proline-catalysed aldol reaction in a ball-mill.
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Scheme 2: Proline-catalysed aldol reaction between solid substrates (1b and 2a).
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Scheme 3: (S)-Binam-L-prolinamide catalysed asymmetric aldol reaction by using a ball-mill. aConversion.
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Scheme 4: Asymmetric aldol reaction assisted by ball-milling catalysed by dipeptides (A) with III and (B) wit...
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Scheme 5: Thiodipeptide-catalysed asymmetric aldol reaction of (A) ketones with aldehydes and (B) acetone wit...
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Scheme 6: Enantioselective Michael reaction of aldehydes with nitroalkenes catalysed by pyrrolidine-derived o...
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Scheme 7: Chiral squaramide catalysed asymmetric Michael reaction assisted by ball-milling.
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Scheme 8: Asymmetric organocatalytic Michael reaction assisted by pestle and mortar grinding.
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Scheme 9: C-2 symmetric thiourea catalysed enantioselective MBH reaction.
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Scheme 10: Quinine-catalysed ring opening of meso-anhydride by ball-milling.
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Scheme 11: Ball-milling-assisted (A) synthesis of glycine schiff bases and (B) their organocatalytic asymmetri...
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Scheme 12: Enantioselective amination of β-ketoester by using pestle and mortar.
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