C–H Functionalization/activation in organic synthesis
The last decade has seen an explosion in research reports in the area of C–H functionalization and activation in organic synthesis. Since organic compounds mainly consist of a carbon skeleton that bears a large number of hydrogens, it is highly desirable to be able to take advantage of the myriad of C–H groups in organic molecules as functional handles for bond formation, and in some cases, bond-breaking processes. In this Thematic Series, a collection of ten contributions from researchers in the area of C–H functionalization from Europe, United States, Japan, China, India, and Brazil is presented. These contributions include full accounts on primary research in the area of C–H functionalization and activation and reviews that focus on aspects of this exciting field.
See also the Thematic Series:
C–H Functionalization
- Full Research Paper
- Published 28 Dec 2015
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Figure 1: Triaryl-2-pyridylidene (PyC) and PyC-gold(I) complex (AuCl(PyC)).
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Figure 2: Yield–time profiles of 4-(4-bromophenyl)-5-methylisoxazole (3ba) and methyl 2-iodobenzoate (5) with...
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Scheme 1: Plausible reaction mechanism of gold-catalyzed oxidative C–H arylation of heteroarenes with arylsil...
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Figure 3: ORTEP drawing of AuCl3(PyC) with 50% probability. Hydrogen atoms and solvent are omitted for clarit...
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Scheme 2: Direct observation and isolation of carbene-gold(III) complex. Mes = 2,4,6-Me3C6H2, Xyl = 2,6-Me2C6H...
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- Full Research Paper
- Published 07 Apr 2016
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Scheme 1: Catalytic C–H borylation of arenes and related reported boron sources.
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Scheme 2: Scalability and derivatization.
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- Review
- Published 13 Apr 2016
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Figure 1: Selected piperazine-containing small-molecule pharmaceuticals.
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Figure 2: Strategies for the synthesis of carbon-substituted piperazines.
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Figure 3: The first α-lithiation of N-Boc-protected piperazines by van Maarseveen et al. in 2005 [37].
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Figure 4: α-Lithiation of N-Boc-N’-tert-butyl piperazines by Coldham et al. in 2010 [38].
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Figure 5: Diamine-free α-lithiation of N-Boc-piperazines by O’Brien, Campos, et al. in 2010 [40].
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Figure 6: The first enantioselective α-lithiation of N-Boc-piperazines by McDermott et al. in 2008 [41].
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Figure 7: Dynamic thermodynamic resolution of lithiated of N-Boc-piperazines by Coldham et al. in 2010 [38].
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Figure 8: Enantioselective α-lithiation of N-Boc-N’-alkylpiperazines by O’Brien et al. in 2013 and 2016 [42,43].
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Figure 9: Asymmetric α-functionalization of N-Boc-piperazines with Ph2CO by O’Brien et al. in 2016 [43].
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Figure 10: A “chiral auxiliary” strategy toward enantiopure α-functionalized piperazines by O’Brien et al. 201...
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Figure 11: Installation of methyl group at the α-position of piperazines by O’Brien et al. 2016 [43].
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Figure 12: α-Lithiation trapping of C-substituted N-Boc-piperazines by O’Brien et al. 2016 [43].
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Figure 13: Rh-catalyzed reactions of N-(2-pyridinyl)piperazines by Murai et al. in 1997 [52].
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Figure 14: Ta-catalyzed hydroaminoalkylation of piperazines by Schafer et al. in 2013 [55].
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Figure 15: Photoredox catalysis for α-C–H functionalization of piperazines by MacMillan et al. in 2011 and 201...
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Figure 16: Copper-catalyzed aerobic C–H oxidation of piperazines by Touré, Sames, et al. in 2013 [67].
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Figure 17: Free radical approach by Undheim et al. in 1994 [68].
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Figure 18: Anodic oxidation approach by Nyberg et al. in 1976 [70].
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- Letter
- Published 19 Apr 2016
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Figure 1: Functionalization of natural peptides and proteins: state of the art.
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Scheme 1: Alkynylation with EBX reagents.
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Scheme 2: Alkynylation of tryptophan-containing peptides.
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- Review
- Published 25 Apr 2016
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Scheme 1: Pathway for transition-metal-catalyzed carbene insertion into C(sp3)–H bonds.
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Scheme 2: Rh(II)-catalyzed site-selective and enantioselective C–H functionalization of methyl ether.
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Scheme 3: Late-stage C–H functionalization with Rh(II)-catalyzed carbene C(sp3)–H insertion.
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Scheme 4: The Rh(II)-catalyzed selective carbene insertion into benzylic C–H bonds.
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Scheme 5: The structure–selectivity relationship.
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Scheme 6: Rh-porphyrin complexes for catalytic intermolecular C–H insertions.
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Scheme 7: Asymmetric intermolecular C(sp3)–H insertion with chiral Rh-porphyrin catalyst.
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Figure 1: The structure of TpM catalysts.
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Scheme 8: Ag-Tpx-catalyzed intermolecular C–H insertion between EDA and alkanes.
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Scheme 9: Ag-Tpx-catalyzed C–H insertion of methane with EDA in scCO2.
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Figure 2: Structure of TpM-type catalysts.
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Scheme 10: Comparison of site-selectivities of C–H insertion in different reaction media.
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Scheme 11: C(sp3)–H bond insertion catalyzed by trinuclear cluster Ag.
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Scheme 12: Zn(II)-catalyzed C(sp3)–H bond insertion.
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- Review
- Published 04 May 2016
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Figure 1: Singlet carbene, triplet carbene and carbenoids.
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Figure 2: Classification of the carbenoid intermediates by the electronic nature of the groups attached to th...
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Figure 3: Chiral bis(oxazoline) ligands used in enantioselective copper carbenoid insertion.
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Scheme 1: Pioneering work of Peter Yates on the carbenoid insertion reaction into X–H bonds (where X = O, S, ...
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Scheme 2: Copper carbenoid insertion into C(sp3)–H bond of a stereogenic center with full retention of the as...
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Scheme 3: Carbenoid insertion into a C(sp3)–H bond as the key step of the Taber’s (+)-α-cuparenone (8) synthe...
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Scheme 4: First enantioselective carbenoid insertion into C–O bonds catalyzed by chiral metallic complexes.
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Figure 4: Chemical structures of complexes (R)-18 and (S)-18.
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Scheme 5: Asymmetric carbenoid insertions into C(sp3)–H bonds of cycloalkanes catalyzed by chiral rhodium car...
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Scheme 6: First diastereo and enantioselective intermolecular carbenoid insertion into tetrahydrofuran C(sp3)...
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Scheme 7: Simplified mechanism of the carbenoid insertion into a C(sp3)–H bond.
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Scheme 8: Nakamura’s carbenoid insertion into a C(sp3)–H bond catalytic cycle.
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Scheme 9: Investigation of the relationship between the electronic characteristics of the substituent X attac...
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Scheme 10: Empirical model to predict the stereoselectivity of the donor/acceptor dirhodium carbenoid insertio...
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Scheme 11: Asymmetric insertion of copper carbenoids in C(sp3)–H bonds to prepare trans-γ-lactam.
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Figure 5: Iridium catalysts used by Suematsu and Katsuki for carbenoid insertion into C(sp3)–H bonds.
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Scheme 12: Chiral porphyrin iridium complex catalyzes the carbenoid insertion into bis-allylic C(sp3)–H bonds.
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Scheme 13: Chiral porphyrin iridium complex catalyzes the carbenoid insertion into tetrahydrofuran C(sp3)–H bo...
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Scheme 14: Chiral porphyrin–iridium complex catalyzes the intramolecular carbenoid insertion into C(sp3)–H bon...
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Scheme 15: Chiral bis(oxazoline)–iridium complex catalyzes the carbenoid insertion into bis-allylic C(sp3)–H b...
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Scheme 16: New cyclopropylcarboxylate-based chiral catalyst to enantioselective carbenoid insertion into the e...
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Scheme 17: Regio- and enantioselective carbenoid insertion into the C(sp3)–H bond catalyzed by a new bulky cyc...
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Scheme 18: Regio and diastereoselective carbenoid insertion into the C(sp3)–H bond catalyzed by a new bulky cy...
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Scheme 19: 2,2,2-Trichloroethyl (TCE) aryldiazoacetates to improve the scope, regio- and enantioselective of t...
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Scheme 20: Sequential C–H functionalization approach to 2,3-dihydrobenzofurans.
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Scheme 21: Enantioselective intramolecular rhodium carbenoid insertion into C(sp3)–H bonds to afford cis-disub...
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Scheme 22: Enantioselective intramolecular rhodium carbenoid insertion into C(sp3)–H bonds to afford cis-2-vin...
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Scheme 23: First rhodium porphyrin-based catalyst for enantioselective carbenoid insertion into C(sp3)–H bond.
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Scheme 24: Rhodium porphyrin-based catalyst for enantioselective carbenoid insertion into benzylic C(sp3)–H bo...
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- Review
- Published 17 May 2016
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Figure 1: Bridged polycyclic natural products.
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Figure 2: Strategic limitations.
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Scheme 1: Bridged rings from N–H bond insertions.
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Scheme 2: The synthesis of deoxystemodin.
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Scheme 3: A model system for ingenol.
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Scheme 4: Formal synthesis of platensimycin.
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Scheme 5: The formal synthesis of gerryine.
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Scheme 6: Copper-catalyzed bridged-ring synthesis.
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Scheme 7: Factors influencing insertion selectivity.
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Scheme 8: Bridged-lactam formation.
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Scheme 9: The total synthesis of (+)-codeine.
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Scheme 10: A model system for irroratin.
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Scheme 11: The utility of 1,6-insertion.
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Scheme 12: Piperidine functionalization.
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Scheme 13: Wilkinson’s catalyst for C–H bond insertion.
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Scheme 14: Bridgehead insertion and the total synthesis of albene and santalene.
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Scheme 15: The total synthesis of neopupukean-10-one.
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Scheme 16: An approach to phomoidride B.
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Scheme 17: Carbene cascade for fused bicycles.
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Scheme 18: Cascade formation of bridged rings.
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Scheme 19: Conformational effects.
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Scheme 20: Hydrazone cascade reaction.
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Scheme 21: Mechanistic studies.
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Scheme 22: Gold carbene formation from alkynes.
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Scheme 23: Au-catalyzed bridged-bicycle formation.
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Scheme 24: Gold carbene/alkyne cascade.
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Scheme 25: Gold carbene/alkyne cascade with C–H bond insertion.
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Scheme 26: Platinum cascades.
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Scheme 27: Tungsten cascade.
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- Full Research Paper
- Published 20 May 2016
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Figure 1: Road map to enhanced C–H activation reactivity.
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Scheme 1: Concerted metalation–deprotonation and elelectrophilic palladation pathways for C–H activation.
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Scheme 2: Routes for generation of cationic palladium(II) species.
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Scheme 3: Optimized conditions for C–H arylations at room temperature.
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Scheme 4: Biaryl formation catalyzed by Pd(OAc)2.
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Figure 2: C–H arylation results. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water (1 mL) with 1...
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Figure 3: Monoarylations in water at rt. Conditions A: Conducted at rt for 20 h in 2 wt % Brij 35/water with ...
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Scheme 5: Selective arylation of a 1-naphthylurea derivative.
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Figure 4: Fujiwara–Moritani coupling rreactions in water. Conditions A: 10 mol % [Pd(MeCN)4](BF4)2, 1 equiv B...
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Figure 5: Optimization. Conducted at rt for 8 h or as otherwise noted in EtOAc with 10 mol % Pd catalyst, AgO...
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Figure 6: Representative results in EtOAc. Conducted at rt in EtOAc with 10 mol % Pd(OAc)2, HBF4 (1 equiv), a...
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Scheme 6: Previous syntheses of boscalid®.
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Scheme 7: Synthesis of boscalid®. aConducted at rt for 20 h in EtOAc with 10 mol % [Pd(MeCN)4](BF4)2, BQ (5 e...
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Scheme 8: Hypothetical reaction sequence for cationic Pd(II)-catalyzed aromatic C–H activation reactions.
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Scheme 9: Palladacycle formation.
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Figure 7: X-ray structure of palladacycle 6 with thermal ellipsoids at the 50% probability level. BF4 and hyd...
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Figure 8: NMR studies. A: The reaction of [Pd(MeCN)4](BF4)2 and 3-MeOC6H4NHCONMe2 in acetone-d6. B: The react...
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Scheme 10: The generation of cationic Pd(II) from Pd(OAc)2.
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Scheme 11: Electrophilic substitution of aromatic hydrogen by cationic palladium(II) species.
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Scheme 12: Attempted reactions of palladacycle 6.
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Scheme 13: The impact of MeCN on C-H activation/coupling reactions.
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Scheme 14: Stoichiometric MeCN-free reactions. a2% Brij 35 was used instead of EtOAc.
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Scheme 15: The reactions of divalent palladacycles.
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Scheme 16: Role of BQ in stoichiometric Fujiwara–Moritani and Suzuki–Miyaura coupling reactions. aYields based...
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Scheme 17: Proposed role of BQ in Fujiwara–Moritani reactions.
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Scheme 18: Proposed role of BQ in Suzuki–Miyaura coupling reactions.
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Scheme 19: Stoichiometric C–H arylation of iodobenzene. aYields based on Pd.
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Scheme 20: Impact of acetate on the cationicity of Pd.
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Scheme 21: Roles of additives in C–H arylation.
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Scheme 22: Cross-coupling in the presence of AgBF4.
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Scheme 23: A proposed catalytic cycle for Fujiwara–Moritani reactions.
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Scheme 24: Proposed catalytic cycle of C–H activation/Suzuki–Miyaura coupling reactions.
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Scheme 25: A proposed catalytic cycle for C–H arylation involving a Pd(IV) intermediate.
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Scheme 26: Selected reactions of divalent palladacycles.
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- Full Research Paper
- Published 08 Jun 2016
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Scheme 1: Synthesis of 2-oxindoles via oxidative processes.
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Figure 1: Substrates scope of one-pot ‘transition-metal-free’ IDC. The syntheses of compounds 4a–s according ...
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Figure 2: Further substrates scope of one-pot ‘transition metal-free’ IDC. Conditions A: KOt-Bu, iodine; cond...
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Figure 3: Substrates scope of ‘transition-metal-free’ IDC using KOt-Bu/I2. Reproduced from [46].
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Figure 4: C-Alkylation of anilides using KOt-Bu.
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Figure 5: Substrates scope of ‘transition-metal-free’ IDC of C-alkylated anilides using DBU/I2.
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Scheme 2: Oxidative coupling of C-arylated anilides (±)-11a–d. The synthesis of 12b as per method A has been ...
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Scheme 3: Synthesis of spirocyclic product through IDC The synthesis of 14 as per method A has been reproduce...
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Scheme 4: Dimerization of β-N-aryl-amidoesters 3a and b. Reproduced from [46].
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Scheme 5: Synthesis of dimeric 2-oxindoles utilizing IDC. The syntheses of 19a and b have been reproduced fro...
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Scheme 6: Plausible mechanism of ‘transition-metal-free’ IDC The mechanistic consideration in Scheme 6 has been repro...
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Scheme 7: Intramolecular-dehydrogenative-coupling (IDC) of 3a and 5a. Reproduced from [46].
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Scheme 8: IDC of 3a and 5a using different oxidants. Reproduced from [46].
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Scheme 9: Synthesis of 3-substituted-2-oxindoles from benzyl esters.
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Scheme 10: 3-Substituted-2-oxindoles from p-methoxybenzyl esters.
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Scheme 11: Synthetic elaboration using Tsuji–Trost reactions. Reproduced from [46].
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- Full Research Paper
- Published 17 Jun 2016
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Scheme 1: New synthetic strategy for THQs via PA-directed C−H functionalization.
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Scheme 2: Preparation of iodo-substituted THQs via PA-directed C−H functionalization strategy. a) ArI (2 equi...
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Scheme 3: Removal of PA auxiliary from THQ product.
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- Full Research Paper
- Published 15 Dec 2016
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Scheme 1: Coordination of Cu(I) with the ambiphilic ligand 1 to form the catalyst 2.
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Scheme 2: Proposed mechanism of direct arylation catalyzed by 2 (X = Cl/I; Ar = aryl).
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