Directed aromatic functionalization
The past decade has witnessed a remarkable growth in the number of organic reactions that are catalyzed by homogeneous gold complexes. Many of the early reported reactions took advantage of the propensity of gold complexes to serve as excellent catalysts for reactions that proceed through π-activation of carbon–carbon multiple bonds. Subsequently, the reactivity paradigms available for gold complexes have proven to be almost limitless. The contributions from many research groups underscore the growing importance of homogenous gold catalysis. More importantly, the papers in this Thematic Series highlight the remarkable breath of reactivity that can be accessed using homogenous gold complexes as catalysts; from catalysis of sigmatropic rearrangement, cycloaddition and cycloisomerization reactions, to applications in enantioselective catalysis, oxidative coupling and the total synthesis of natural products, and transformations of alkynes, allenes, alkenes and even C–H bonds.
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Scheme 1: Lithiation and substitution of isoindolin-1-ones [43].
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Scheme 2: Lithiation and cyclization of N-tert-butyl-N-benzylbenzamides [45].
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Scheme 3: Lithiation and substitution of 1 at −20 °C [69].
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Figure 1: Structures of 4–6.
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Scheme 4: A possible mechanism for the formation of 6.
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Figure 2: X-Ray crystal structures of crystallized compounds 12 and 15–18.
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Figure 3: Structures of compounds 41–44.
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Figure 4: X-ray crystal structures of compounds 38 and 39.
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- Published 06 Sep 2011
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Scheme 1: Synthesis of potent antiviral and antitumor cyclonucleosides 5.
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Figure 1: Lithiation of 2',3'-O-isopropylideneuridine (6).
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Figure 2: Metalation of 5'-O-TMDMS protected nucleoside 10.
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Figure 3: Lithiation/alkylation of 2',3',5'-tri-O-benzoyl-3,6-dimethyluridine (13) using LDA.
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Scheme 2: Preparation of 2',3'-O-isopropylidene-5'-O-(tert-butyldimethylsilyl)-6-methyluridine (2).
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Scheme 3: Lateral lithiation/alkylation of 6-methyluridine 2.
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Figure 4: Bis-allylated products 20 and 21.
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Scheme 1: Proposed stepwise mechanism for the zincation of benzene.
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Figure 1: Molecular structure of 2 with selective atom labelling. Hydrogen atoms and minor disorder component...
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Scheme 2: Synergic metallation of N,N-dimethylaniline (A) with sodium TMP-zincate 1 to produce 2, which was s...
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Figure 2: Molecular structure of 3 with selective atom labelling and thermal ellipsoids drawn at the 50% prob...
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Scheme 3: Indirect zincation of N,N-dimethylaniline producing 4, 5 and 6, which was then quenched with I2 to ...
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Figure 3: Molecular structure of 4 with selective atom labelling and thermal ellipsoids drawn at the 50% prob...
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Figure 4: Solvent-separated ion-pair structure of 5 with selective atom labelling and thermal ellipsoids draw...
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Figure 5: Molecular structure of 6 with selective atom labelling and thermal ellipsoids drawn at the 50% prob...
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Figure 6: Aromatic region of 1H NMR spectra for deuterated benzene solutions of (a) the crude mixture obtaine...
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Figure 7: Relative energy sequence of the four theoretical regioisomers of the experimentally observed produc...
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- Published 09 Sep 2011
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Scheme 1: Selective benzylic metalation with LiNK conditions. DG = directing group.
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Scheme 2: Iterative LiNK/oxidative coupling synthesis of [2.2]metacyclophanes.
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Figure 1: Xylene substrates.
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Figure 2: Metalation selectivity for 4e (arrows indicate potential metalation sites). 2H NMR spectrum in CH2Cl...
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Figure 3: Di-metalation selectivity for 6f. 2H NMR spectrum in CH2Cl2. *CD2Cl2.
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Figure 4: X-Ray structure of 8c with thermal ellipsoids drawn at 50% probability level.
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- Published 12 Sep 2011
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Figure 1: Some representative dihydroxybenzofuran derived natural products.
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Scheme 1: Retrosynthetic analysis of 4,n-dimethoxy-substituted benzo[b]furans.
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Scheme 2: Deprotonative zincation of 3-haloanisoles 1.
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- Review
- Published 13 Sep 2011
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Scheme 1: Preparation of polyfunctional heteroarylzinc reagents.
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Scheme 2: LiCl-mediated insertion of zinc dust to aryl and heteroaryl iodides.
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Scheme 3: Selective insertions of Zn in the presence of LiCl.
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Scheme 4: Chemoselective insertion of zinc in the presence of LiCl.
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Scheme 5: Preparation and reactions of benzylic zinc reagents.
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Scheme 6: Ni-catalyzed cross-coupling of benzylic zinc reagent 34 with ethyl 2-chloronicotinate.
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Scheme 7: In situ generation of arylzinc reagents using Mg in the presence of LiCl and ZnCl2.
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Scheme 8: Zincation of heterocycles with TMP2Zn (42).
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Scheme 9: Preparation of highly functionalized zincated heterocycles using TMP2Zn·2MgCl2·2LiCl (42).
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Scheme 10: Microwave-accelerated zincation of heterocycles using TMP2Zn·2MgCl2·2LiCl (42).
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Scheme 11: The I/Mg-exchange as a metal-metathesis reaction.
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Scheme 12: Regioselective Br/Mg-exchange of dibromoquinolines 65 and 68.
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Scheme 13: Improved reagents for the regioselective Br/Mg-exchange on bromoquinolines.
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Scheme 14: Synthesis of ellipticine (83) using an I/Mg-exchange reaction.
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Scheme 15: An oxidative amination leading to the biologically active adenine, purvalanol A (84).
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Scheme 16: Preparation of polyfunctional arylmagnesium reagents using Mg in the presence of LiCl.
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Scheme 17: Preparation of polyfunctional magnesium reagents starting from organic chlorides.
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Scheme 18: Selective multiple magnesiation of the pyrimidine ring.
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Scheme 19: Synthesis of a p38 kinase inhibitor 119 and of a sPLA2 inhibitor 123.
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Scheme 20: Synthesis of highly substituted indoles of type 128.
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Scheme 21: Efficient magnesiations of polyfunctional aromatics and heterocycles using TMP2Mg·2LiCl (129).
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Scheme 22: Negishi cross-coupling in the presence of substrates bearing an NH- or an OH-group.
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Scheme 23: Negishi cross-coupling in the presence of a serine moiety.
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Scheme 24: Radical catalysis for the performance of very fast Kumada reactions.
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Scheme 25: MgCl2-mediated addition of functionalized aromatic, heteroaromatic, alkyl and benzylic organozincs ...
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Figure 1: Modular synthesis of bis(diarylphosphino)-, bis(dialkylphosphino)- and dialkyl(diaryl)phosphinobiph...
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Figure 2: ARYNE coupling.
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Scheme 1: Functionalization of 2,2',6-tribromobiphenyl (1a) by regioselective bromine–lithium exchange.
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Scheme 2: Functionalization of 2,2'-dibromobiphenyls (1b–e) by regioselective bromine–lithium exchange.
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Figure 3: General access to biaryl mono- and diphosphine ligands; (Cy = cyclohexyl).
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Scheme 3: Synthesis of monophosphines 3; (Cy = cyclohexyl).
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Figure 4: Molecular structure of compound 3a (crystallized from ethyl acetate/hexane) [74].
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Scheme 4: Preparation of mixed dialkyl(diaryl)phosphinobiphenyls 5 via successive bromine–lithium exchange.
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Scheme 5: Stepwise bromine–lithium exchange on 1c.
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- Published 22 Sep 2011
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Figure 1: Chiral diols useful for asymmetric synthesis and the tetralithio intermediate 8.
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Scheme 1: Directed ortho,ortho'-dimetalation of (R,R)-hydrobenzoin (3).
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Figure 2: Percentage of (R,R)-hydrobenzoin (3) (○), monodeuterohydrobenzoin (13) (■), and dideuterohydrobenzo...
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Figure 3: Percentage of methylhydrobenzoin (14) (■), and dimethylhydrobenzoin (15) (Δ) as determined by 1H NM...
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Scheme 2: Formation of the tetralithio intermediate 8 and the X-ray crystal structure of the bis(siloxane) 19....
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Scheme 3: Reaction of the tetralithio intermediate 8 with various electrophiles.
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Scheme 4: Reactions of the diiodohydrobenzoin 12 and X-ray crystal structure of the dihydrosilepin 31.
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Scheme 5: Cross coupling reactions of the bis(benzoxaborol) 20 and a short formal synthesis of (R,R)-Vivol (4...
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- Published 26 Sep 2011
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Scheme 1: Desymmetrising metallation for the enantioselective synthesis of atropisomers.
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Scheme 2: Benzylic lithiation of a diaryl ether.
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Scheme 3: Benzylic metallation of a diaryl ether α to a carbamate.
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Scheme 4: Diastereo- and enantioselective synthesis of atropisomeric ethers by benzylic lithiation.
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Scheme 5: Atroposelective stannylation.
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Scheme 6: Stereospecific tin–lithium exchange/quench reactions.
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Scheme 7: Proposed stereochemical pathway.
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- Published 28 Oct 2011
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Scheme 1: Structure and retrosynthetic analysis of fredericamycin A.
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Scheme 2: Assembly of the isoquinolone segment of fredericamycin.
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Scheme 3: Synthesis of a naphthalide precursor to the quinoid moiety of fredericamycin.
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Scheme 4: Palladium-mediated cyclization of a fredericamycin model system.
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Scheme 5: Synthesis of the precursor of fredericamycin and the facile air oxidation thereof.
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Scheme 6: Formal synthesis of fredericamycin A.
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Figure 1: Structure of nothapodytine B.
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Scheme 7: A useful pyridone synthesis.
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Scheme 8: Retrosynthetic logic for nothapodytine B.
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Scheme 9: Preparation of a key nothapodytine fragment.
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Scheme 10: Total synthesis of nothapodytine B.
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Figure 2: Structures of topopyrones.
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Scheme 11: Retrosynthetic logic for the linear series of topopyrones.
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Scheme 12: Construction of the molecular subunit common to all topopyrones.
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Scheme 13: Difficulties encountered during the merger of the topopyrone D moieties.
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Scheme 14: Efficient synthesis of a simplified anthraquinone.
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Scheme 15: Total synthesis of topopyrone D.
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Scheme 16: Total synthesis of topopyrone B.
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- Published 25 Nov 2011
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Scheme 1: 3-Component coupling reactions of arynes. E+ = electrophile.
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Scheme 2: Aryne mediated α-arylation of amino acids. DMG = directed metallation group. BHT = 2,6-di-tert-buty...
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Scheme 3: Proposed mechanism of α-arylation.
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Scheme 4: Proposed extension of the methodology to synthesize quaternary adducts.
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Scheme 5: Formation of α-methyl, α-aryl Schöllkopf adduct.
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Figure 1: NOESY correlation observed for 6a.
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Figure 2: X-ray crystal structure of 6b.
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Figure 3: Transition state analysis to explain the lack of diastereoselectivity at C-2.
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Scheme 6: Formation of quaternary adducts.
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Scheme 7: Hydrolysis of quaternary adducts.
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Scheme 8: Hydrolysis to amino acids.
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Scheme 9: Hydrolysis of analogue 6j.
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Scheme 10: Epimerization at C-3 of 6g.
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- Published 29 Nov 2011
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Scheme 1: Stoichiometric and catalytic direct (hetero)arylation of arenes.
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Scheme 2: Stille and Negishi cross-coupling methodologies in oxazole series [28,30,31,33,34].
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Scheme 3: Stoichiometric direct (hetero)arylation of (benz)oxazole with magnesate bases [35].
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Scheme 4: Ohta's pioneering catalytic direct C5-selective pyrazinylation of oxazole [36,37].
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Scheme 5: Preparation of pharmaceutical compounds by following the pioneering Ohta protocol [38,39].
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Scheme 6: Miura’s pioneering catalytic direct arylations of (benz)oxazoles [40]. aIsolated yield.
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Scheme 7: Pd(0)- and Cu(I)-catalyzed direct C2-selective arylation of (benz)oxazoles [41-44].
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Scheme 8: Cu(I)-catalyzed direct C2-selective arylations of (benz)oxazoles [40,45-47].
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Scheme 9: Copper-free Pd(0)-catalyzed direct C5- and C2-selective arylation of oxazole-4-carboxylate esters [48-50,52].
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Scheme 10: Iterative synthesis of bis- and trioxazoles [51].
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Scheme 11: Preparation of DPO- and POPOP-analogues [53].
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Scheme 12: Pd(0)-catalyzed direct arylation of benzoxazole with aryl chlorides [54].
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Scheme 13: Pd(0)-catalyzed direct C2-selective arylation of (benz)oxazoles with bromides and chlorides using b...
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Scheme 14: Palladium-catalyzed direct arylation of oxazoles under green conditions; (a) Zhuralev direct arylat...
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Scheme 15: Pd(0)-catalyzed C2- and C5-selective (hetero)arylation of oxazole [63].
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Scheme 16: Pd(0)-catalyzed C2- and C5-selective (hetero)arylation of ethyl oxazole-4-carboxylate [64].
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Scheme 17: Pd(0)-catalyzed direct C4-phenylation of oxazoles; (a) Miura’s procedure [65]; (b) Fagnou’s procedure [66].
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Scheme 18: Catalytic cycles for Cu(I)-catalyzed (routeA) and Pd(0)/Cu(I)-catalyzed (route B) direct arylation ...
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Scheme 19: Base-assisted, Pd(0)-catalyzed, C2-selective, direct arylation of benzoxazole proposed by Zhuralev [58]...
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Scheme 20: Electrophilic substitution-type mechanism proposed by Hoarau [64].
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Scheme 21: CMD-proceeding C5-selective direct arylation of oxazole proposed by Strotman and Chobabian [63].
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Scheme 22: DFT calculations on methyl oxazole-4-carboxylate and consequently developed methodologies for the P...
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Scheme 23: Pd(0)-catalyzed direct arylation of (benz)oxazoles with tosylates and mesylates [71].
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Scheme 24: Pd(0)-catalyzed direct arylation of oxazoles with sulfamates [72].
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Scheme 25: Pd(II)- and Cu(II)-catalyzed decarboxylative direct C–H coupling of oxazoles with 4- and 5-carboxyo...
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Scheme 26: Pd(II)- and Ag(II)-catalyzed decarboxylative direct arylation of (benzo)oxazoles [74]; (a) procedure; (...
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Scheme 27: Pd(II)- and Cu(II)-catalyzed direct arylation of benzoxazole with arylboronic acids [76]; (a) procedure...
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Scheme 28: Ni(II)-catalyzed direct arylation of benzoxazoles with arylboronic acids under O2 [76]; (a) procedure; ...
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Scheme 29: Rhodium-catalyzed direct arylation of benzoxazole [78,79].
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Scheme 30: Ni(II)-catalyzed direct arylation of (benz)oxazoles with aryl halides; (a) Itami's procedure [80]; (b) ...
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Scheme 31: Dehydrogenative cross-coupling of (benz)oxazoles; (a) Pd(II)- and Cu(II)-catalyzed cross-coupling o...
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On the control of secondary carbanion structure utilising ligand effects during directed metallation
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Scheme 1: Molecular structures of 1/2-H and their corresponding ortho-lithiates [21].
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Scheme 2: Molecular structures of 3/4-H and their corresponding lateral lithiates [23,24].
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Scheme 3: Conversion of kinetic ortho-lithiate into the thermodynamic lateral lithiate under the influence of...
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Scheme 4: Molecular structure of 5-H and its lateral and ortho-lithiates [20].
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Scheme 5: Lateral metallation of 6-H using t-BuLi in the presence of Lewis base L.
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Figure 1: Molecular structure of 6-Lil·PMDTA; H-atoms (excl. H8) omitted for clarity. Selected bond lengths (...
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Scheme 6: Comparison of aromatic and aryl–(α-C) bond distances in 5-Lil·L [20] and 6-Lil·L (L = PMDTA).
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Figure 2: Molecular structure of 6-Lil·DGME; H-atoms omitted. Selected bond lengths (Å) and angles (°): O1–Li...
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Figure 3: Computed minimum energy conformers (B3LYP density functional/6-311++G(2d,2p) basis set; H-atoms omi...
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