Copper-Promoted N-Arylation of the Imidazole Side Chain of Protected Histidine by Using Triarylbismuth Reagents

The N-arylation of the side chain of histidine by using triarylbismuthines is reported. The reaction is promoted by copper(II) acetate in dichloromethane at 40 °C under oxygen in the presence of diisopropylethylamine and 1,10-phenanthroline and allows the transfer of aryl groups with substituents at any position of the aromatic ring. The reaction shows excellent functional group tolerance and is applicable to dipeptides where the histidine is located at the N terminus. A histidine-guided backbone N−H arylation was observed in dipeptides where the histidine occupies the C terminus.     

A facile route to flavone and neoflavone backbones via a regioselective palladium catalyzed oxidative Heck reaction

A straightforward and atom-economical base-free palladium-catalyzed regioselective direct arylation of coumarins and chromenones is devised. This protocol is compatible with a wide variety of electron-donating and -withdrawing substituents and allows construction of various biologically important flavone and neoflavone backbones.     

Short and Efficient Syntheses of Protoberberine Alkaloids using Palladium‐Catalyzed Enolate Arylation

A concise synthesis of the biologically active alkaloid berberine is reported, and a versatile palladium‐catalyzed enolate arylation is used to form the isoquinoline core. The overall yield of 50 % is a large improvement over the single, previous synthesis. By design, this modular route allows the rapid synthesis of other members of the protoberberine family (e.g., pseudocoptisine and palmatine) by substitution of the readily available aryl bromide and ketone coupling partners. Moreover, by combining enolate arylation with in situ functionalization, substituents can be rapidly and regioselectively introduced at the alkaloid C13 position, as demonstrated by the total synthesis of dehydrocorydaline. The avoidance of electrophilic aromatic substitution reactions to make the isoquinoline allows direct access to analogues possessing more varied electronic properties, such as the fluorine‐containing derivative synthesized here.     

Proton-abstraction mechanism in the palladium-catalyzed intramolecular arylation: substituent effects

The regioselectivity observed in the intramolecular palladium-catalyzed arylation of substituted bromobenzyldiarylmethanes as well as theoretical results demonstrate that the Pd-catalyzed arylation proceeds by a mechanism involving a proton abstraction by the carbonate, or a related basic ligand. The reaction is facilitated by electron-withdrawing substituents on the aromatic ring, which is inconsistent with an electrophilic aromatic-substitution mechanism. The more important directing effect is exerted by electron-withdrawing substituents ortho to the reacting site.     

Facile and general synthesis of quaternary 3-aminooxindoles

A novel approach to the valuable quaternary 3-aminooxindole skeleton is reported on the basis of intramolecular arylation of enolates of substituted amino acids. The reaction tolerates dialkyl- and arylalkylamines as well as a range of carbon substituents (primary and secondary alkyl, aryl). The cyclization of N-indolyl-substituted substrates is accompanied by direct C-H arylation of the indole, leading to indolo-fused benzodiazepines.     

Palladium-catalyzed direct arylation of 5-chloropyrazoles: a selective access to 4-aryl pyrazoles

The use of a temporary protection by a chloro group at C5 of pyrazoles allows the synthesis of the 4-arylated pyrazoles, which were previously inaccessible by palladium-catalyzed direct arylation, with complete regioselectivity and in high yields using in most cases as little as 0.5-0.1 mol % Pd(OAc)(2) as the catalyst with electron-deficient aryl bromides. Moreover, from 5-chloro-1,3-dimethylpyrazole, sequential catalytic C4 arylation, dechlorination, catalytic C5 arylation reactions allowed the synthesis of a 4,5-diarylated pyrazole derivative.     

Heteroatom‐Guided,Palladium‐Catalyzed,Site‐Selective CH Arylation of 4H‐Chromenes: Diastereoselective Assembly of the Core Structure of Myristinin B through Dual CH Functionalization

A highly site‐selective, heteroatom‐guided, palladium‐catalyzed direct arylation of 4H‐chromenes is reported. The C?H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C?H functionalization strategy for regioselective direct arylation.     

Radical C?H Arylation of the BODIPY Core with Aryldiazonium Salts: Synthesis of Highly Fluorescent Red‐Shifted Dyes

We describe herein the first radical C H arylation of BODIPY dyes. This novel, general, one‐step synthetic procedure uses ferrocene to generate aryl radical species from aryldiazonium salts and allows the straightforward synthesis of brightly fluorescent (Φ>0.85) 3,5‐diarylated and 3‐monoarylated boron dipyrrins in up to 86 % yield for a broad range of aryl substituents. In this way, new and complex dyes with red‐shifted spectra can be easily prepared.     

Radical CH Arylation of the BODIPY Core with Aryldiazonium Salts: Synthesis of Highly Fluorescent Red‐Shifted Dyes

We describe herein the first radical C? H arylation of BODIPY dyes. This novel, general, one‐step synthetic procedure uses ferrocene to generate aryl radical species from aryldiazonium salts and allows the straightforward synthesis of brightly fluorescent (Φ>0.85) 3,5‐diarylated and 3‐monoarylated boron dipyrrins in up to 86 % yield for a broad range of aryl substituents. In this way, new and complex dyes with red‐shifted spectra can be easily prepared.     

N‐Arylation of Diketopyrrolopyrroles with Aryl Triflates

A new methodology for the double N‐arylation of diketopyrrolopyrroles with aryl triflates has been developed. It is now possible to prepare diketopyrrolopyrroles bearing N‐substituents derived from naphthalene, anthracene and coumarin in two steps from commercially available phenols. This represents the first time arenes lacking strong electron‐withdrawing groups were inserted onto lactamic nitrogen atoms via arylation. The ability to incorporate heretofore unprecedented substituents translates to increased modulation of the resulting photophysical properties such as switching‐on/off solvatofluorochromism. TD‐DFT calculations have been performed to explore the nature of the relevant excited states. This new synthetic method made it possible to elucidate the influence of such substituents on the absorption and emission properties of tetraaryl substituted diketopyrrolopyrroles.     

Phase‐Transfer‐Catalyzed Asymmetric SNAr Reaction of α‐Amino Acid Derivatives with Arene Chromium Complexes

Although phase‐transfer‐catalyzed asymmetric S_NAr reactions provide unique contribution to the catalytic asymmetric α‐arylations of carbonyl compounds to produce biologically active α‐aryl carbonyl compounds, the electrophiles were limited to arenes bearing strong electron‐withdrawing groups, such as a nitro group. To overcome this limitation, we examined the asymmetric S_NAr reactions of α‐amino acid derivatives with arene chromium complexes derived from fluoroarenes, including those containing electron‐donating substituents. The arylation was efficiently promoted by binaphthyl‐modified chiral phase‐transfer catalysts to give the corresponding α,α‐disubstituted α‐amino acids containing various aromatic substituents with high enantioselectivities.     

C-H arylation of pyridines: high regioselectivity as a consequence of the electronic character of C-H bonds and heteroarene ring

We report a new catalytic protocol for highly selective C-H arylation of pyridines containing common and synthetically versatile electron-withdrawing substituents (NO(2), CN, F and Cl). The new protocol expands the scope of catalytic azine functionalization as the excellent regioselectivity at the 3- and 4-positions well complements the existing methods for C-H arylation and Ir-catalyzed borylation, as well as classical functionalization of pyridines. Another important feature of the new method is its flexibility to adapt to challenging substrates by a simple modification of the carboxylic acid ligand or the use of silver salts. The regioselectivity can be rationalized on the basis of the key electronic effects (repulsion between the nitrogen lone pair and polarized C-Pd bond at C2-/C6-positions and acidity of the C-H bond) in combination with steric effects (sensitivity to bulky substituents).     

C−H Bond Arylation of Pyrazoles at the β-Position: General Conditions and Computational Elucidation for a High Regioselectivity

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β-position of pyrazoles, while C−H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via β-C−H bond functionalization. The β-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at β-position of the pyrazoles and thus favors this direct β-C−H bond arylation. This selective pyrazoles β-C−H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom-economical process.     

Azaphilic versus Carbophilic Coupling at CN Bonds: Key Steps in Titanium‐Assisted Multicomponent Reactions

Consecutive C‐ and N‐arylation of N‐heterocyclic nitriles is mediated by titanium(IV) alkoxides. The carbo‐ and azaphilic arylation step may be separated by choosing the order in which the two equivalents of aryl transfer reagent are added. In the course of this transformation, the ancillary N‐heterocycle acts as both a directing anchor group and electron reservoir. In the selectivity‐determining step, the selectivity is governed by a choice between (direct) C‐ and Ti‐arylation; the latter opens up a reaction pathway that allows further migration to the nitrogen atom. The isolation of metal‐containing aggregates from the reaction mixture and computational studies gave insights into the reaction mechanism. Subsequently, a multicomponent one‐pot protocol was devised to rapidly access complex quaternary carbon centers.     

二茂铁亚胺环钯化合物催化的带有导向基团的sp2C—H键底物的邻位芳基化

发展了一种以二茂铁亚胺环钯化合物为催化剂, 对带有导向基团的sp2 C—H键芳基底物进行邻位芳基化的新颖高效的催化体系. 实验结果表明, 反应表现出明显的区域选择性, 芳基化只发生在空间位阻较小的sp2 C—H键上, 反应可以采用多种取代基(如CH3O, CH3CO, Br和Cl)进行, 这有助于通过进一步反应构建更为复杂的新化合物.     

Synthesis of helicenes utilizing palladium-catalyzed double C-H arylation reaction

[5]- and [6]helicenes were synthesized in moderate to good yields from Z,Z-bis(bromostilbene)s by palladium-catalyzed double C-H arylation reaction. This method can be applied to the syntheses of helicenes possessing electron-deficient substituents.     

Development of Modifiable Bidentate Amino Oxazoline Directing Group for Pd‐Catalyzed Arylation of Secondary CH Bonds

A novel bidentate α‐amino oxazolinyl directing group has been developed. Different from previous directing groups, this newly designed directing group was easily prepared from amino acids and modified in structure. This auxiliary preferentially effects functionalization at secondary C(sp³)?H bonds, rather than at aryl C(sp²)?H bonds. The diastereoselectivity of direct arylation between geminal secondary C(sp³)?H bonds in linear molecules has also been realized for the first time with a chiral directing group by remote chirality relay. Two diastereoisomers are produced with the same chiral source by changing the substituents of substrates and aryl halides.     

Origins of regioselectivity in radical arylation of aniline: A computational study

The radical arylation of the para‐substituted anilines under three different conditions (A: arylhydrazines as the radical precursors and MnO₂ as the oxidant in acetonitrile; B: arylhydrazine hydrochlorides as the radical precursors and O₂ as the oxidant in aqueous sodium hydroxide solution; C: arenediazonium salts as the radical precursors and TiCl₃ as the reductant in aqueous hydrochloric acid solution) has been theoretically studied and the origins of the ortho/meta regioselectivity have been explored. The arylation process is suggested to contain three steps: radical generation, radical addition, and rearomatization. Calculations show that the arylation of the neutral anilines is kinetically controlled under conditions A and B, and the regioselectivity is determined by the radical addition. As a directing group, ? NH₂ plays an important role in these cases with the assistance of Mn(OH)₂ (the reduced product of MnO₂ under condition A) and Na⁺ (condition B). As for the arylation of the protonated anilines under condition C, the regioselectivity is affected by the substituents in the para‐position of anilines. Electron‐donating groups support meta‐addition and the selectivity is decided by the radical addition. Conversely, electron‐withdrawing groups favor ortho‐addition, and in this situation the arylation process is thermodynamically controlled and the regioselectivity is determined by the radical addition and rearomatization. © 2015 Wiley Periodicals, Inc.     

Rate and Computational Studies for Pd-NHC-Catalyzed Amination with Primary Alkylamines and Secondary Anilines: Rationalizing Selectivity for Monoarylation versus Diarylation with NHC Ligands

The relative rates of arylation of primary alkylamines with different Pd-NHC catalysts have been measured, as have the relative rates of arylation of the secondary aniline product in an attempt to understand the key ligand design features necessary to have high selectivity for the monoarylated amine product. As the substituents on the N-aryl ring of the NHC increase in size, selectivity for monoarylation increases and this is further enhanced by chlorinating the back of the NHC ring. Computations have been performed on the catalytic cycle of this transformation in order to understand the selectivity obtained with the different catalysts.     

On the mechanism of the palladium-catalyzed β-arylation of ester enolates

The palladium‐catalyzed β‐arylation of ester enolates with aryl bromides was studied both experimentally and computationally. First, the effect of the ligand on the selectivity of the α/β‐arylation reactions of ortho‐ and meta‐fluorobromobenzene was described. Selective β‐arylation was observed for the reaction of o‐fluorobromobenzene with a range of biarylphosphine ligands, whereas α‐arylation was predominantly observed with m‐fluorobromobenzene for all ligands except DavePhos, which gave an approximate 1:1 mixture of α‐/β‐arylated products. Next, the effect of the substitution pattern of the aryl bromide reactant was studied with DavePhos as the ligand. We showed that electronic factors played a major role in the α/β‐arylation selectivity, with electron‐withdrawing substituents favoring β‐arylation. Kinetic and deuterium‐labeling experiments suggested that the rate‐limiting step of β‐arylation with DavePhos as the ligand was the palladium–enolate‐to‐homoenolate isomerization, which occurs by a β? H‐elimination, olefin‐rotation, and olefin‐insertion sequence. A dimeric oxidative‐addition complex, which was shown to be catalytically competent, was isolated and structurally characterized. A common mechanism for α‐ and β‐arylation was described by DFT calculations. With DavePhos as the ligand, the pathway leading to β‐arylation was kinetically favored over the pathway leading to α‐arylation, with the palladium–enolate‐to‐homoenolate isomerization being the rate‐limiting step of the β‐arylation pathway and the transition state for olefin insertion its highest point. The nature of the rate‐limiting step changed with PCy₃ and PtBu₃ ligands, and with the latter, α‐arylation became kinetically favored. The trend in selectivity observed experimentally with differently substituted aryl bromides agreed well with that observed from the calculations. The presence of electron‐withdrawing groups on these bromides mainly affected the α‐arylation pathway by disfavoring C? C reductive elimination. The higher activity of the ligands of the biaryldialkylphosphine ligands compared to their corresponding trialkylphosphines could be attributed to stabilizing interactions between the biaryl backbone of the ligands and the metal center, thereby preventing deactivation of the β‐arylation pathway.