Converting gem-dimethyl groups into cyclopropanes via Pd-catalyzed sequential C-H activation and radical cyclization

A novel route to the synthesis of cyclopropane derivatives is described. 1,1-Dimethyls in 2-(1,1-dimethylalkyl)dimethyloxazolines are first converted into 1,3-diiodide derivatives via Pd-catalyzed sequential C-H activation and then radically cyclized to provide 2-(1-alkylcylclopropyl)dimethyloxazolines. The use of EtOAc as a solvent is crucial for the diiodination of the functionalized substrates. [reaction: see text]     

Synthesis of dihydropyridines and pyridines from imines and alkynes via C-H activation

A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence has been developed for the synthesis of highly substituted pyridine derivatives from alkynes and alpha,beta-unsaturated N-benzyl aldimines and ketimines that proceeds through dihydropyridine intermediates. A new class of ligands for C-H activation was developed, providing broader scope for the alkenylation step than could be achieved with previously reported ligands. Substantial information was obtained about the mechanism of the reaction. This included the isolation of a C-H activated complex and its structure determination by X-ray analysis; in addition, kinetic simulations using the Copasi software were employed to determine rate constants for this transformation, implicating facile C-H oxidative addition and slow reductive elimination steps.     

Synthesis of dibenzofurans via palladium-catalyzed phenol-directed C-H activation/C-O cyclization

A practical, Pd(0)/Pd(II)-catalyzed reaction was developed for phenol-directed C-H activation/C-O cyclization using air as an oxidant. The turnover-limiting step of the process was found to be C-O reductive elimination instead of C-H activation. This reaction can tolerate a variety of functional groups and is complementary to the previous methods for the synthesis of substituted dibenzofurans.     

Pd-catalyzed alkyl to aryl migration and cyclization: an efficient synthesis of fused polycycles via multiple C-H activation

A novel palladium migration methodology for the synthesis of complex fused polycycles has been developed. This process involves 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecular Heck reaction providing a very efficient way to synthesize fused ring systems.     

Synthesis of indolo [1,2-a]quinoxalines via a Pd-catalyzed regioselective C-H olefination/cyclization sequence

A highly efficient approach to indolo [1,2-a]quinoxaline derivatives through a Pd-catalyzed regioselective C-H olefination/cyclization sequence has been developed. This transformation has a wide range of substrates with various functional groups, and the corresponding heterocyclic products were obtained in good yields.     

Synthesis of dihydroindenofuran scaffold via a Pd-catalyzed 5-endo-trig cyclization/enolate O-alkylation cascade

An efficient synthesis of dihydroindenofurans was carried out starting from the Baylis-Hillman adducts via a Pd-catalyzed 5-endo-trig-carbopalladation and enolate O-alkylation cascade as a key step. This is the first example of enolate O-alkylation with a C(sp³)-bound palladium intermediate.     

Synthesis of sterically congested bicyclic tetrahydrofurans via Pd-catalyzed cyclization

Prins-type cyclization followed by palladium-catalyzed cyclization provided sterically congested bi- or tricyclic tetrahydrofurans, which are very stereoselective as well. cis-2,5-Disubstituted tetrahydrofurans obtained from Prins-type cyclization have an allenyl group and a functional group such as alcohol, carboxylic acid, and aryl halide. The tetrahydrofurans bearing an allene group underwent palladium-catalyzed cyclization to give sterically congested bi- or tricyclic tetrahydrofurans.     

Synthesis of cyclopropanes by Pd-catalyzed activation of alkyl C-H bonds

A novel synthesis of cyclopropanes has been developed via palladium-catalyzed C-H activation in which two new carbon-carbon bonds are formed in a single step. This method involves palladium-catalyzed activation of normally unreactive secondary alkyl C-H bonds and provides an efficient way to access cyclopropapyrrolo[1,2-a]indoles, analogues of mitomycin and cyclopropamitosenes.     

Synthesis of E-vinyl iodides via Pd-catalyzed hydrostannation of terminal alkynes

E-Vinyl iodides may be prepared via a one-pot reaction involving Pd-catalyzed hydrostannation of terminal alkynes followed by iodinolysis of the intermediate vinylstannane. The synthesis is tolerant of functional groups, such as alcohols and esters.     

Synthesis of catechols from phenols via Pd-catalyzed silanol-directed C-H oxygenation

A silanol-directed, Pd-catalyzed C-H oxygenation of phenols into catechols is presented. This method is highly site selective and general, as it allows for oxygenation of not only electron-neutral but also electron-poor phenols. This method operates via a silanol-directed acetoxylation, followed by a subsequent acid-catalyzed cyclization reaction into a cyclic silicon-protected catechol. A routine desilylation of the silacyle with TBAF uncovers the catechol product.     

Synthesis of benzofurans via Pd-catalyzed oxidative cyclization of 2-allylphenols

Substituted 2-methylbenzofurans were obtained from 2-allylphenols via Pd²⁺-catalyzed oxidative cyclization using Cu(OAc)₂–LiCl as a reoxidant and wet DMF as a solvent.     

Pd-catalyzed cascade cyclization of allenylethylene carbonates and indandiones: Synthesis of tetracyclic dihydrocyclopentaindenofuranone derivatives

A palladium-catalyzed cascade cyclization of allenylethylene carbonates with 1,3-indandiones was developed, providing biologically interesting tetracyclic dihydrocyclopentaindenofuranone derivatives having three contiguous quaternary carbon centers in moderate to high yields with excellent diastereoselectivities. In this reaction, the allene moiety was fully fused into the cyclopentene ring.     

Synthesis of 1,2,3-triazole-fused heterocycles via Pd-catalyzed cyclization of 5-iodotriazoles

A convenient approach toward polycyclic frameworks containing fused 1,2,3-triazoles is described. The synthesis consists of a Cu-catalyzed cycloaddition and an intramolecular Pd-catalyzed direct arylation or Heck reaction, and affords the products in good to excellent yields.     

Synthesis of condensed pyrroloindoles via Pd-catalyzed intramolecular C-H bond functionalization of pyrroles

A new strategy for the synthesis of condensed hetero- or carbocycles such as pyrroloindoles or fluorenes has been developed that involves the Pd-catalyzed cyclization of readily available N-(2-halobenzyl)pyrroles or their phenyl derivatives. The reaction is proposed to proceed via oxidative addition of benzylic halides to Pd(0) followed by base-assisted C-H bond activation. A broad range of condensed cyclic products could be obtained in good to excellent yields under mild conditions.     

Synthesis of propargylic and allenic carbamates via the C-H amination of alkynes

Propargylic amines are important intermediates for the synthesis of nitrogen-containing heterocycles. The insertion of a nitrene into a propargylic C-H bond has not been explored, despite the attention directed toward the Rh-catalyzed amination of other types of C-H bonds. In this communication, the conversion of a series of homopropargylic carbamates to propargylic carbamates and aminated allenes is described.     

Synthesis of pyridines from ketoximes and terminal alkynes via C-H bond functionalization

An expedient one-pot rhodium catalyzed C-H bond functionalization/electrocyclization/dehydration procedure has been developed for the synthesis of highly substituted pyridine derivatives from terminal alkynes and α,β-unsaturated ketoximes. The use of electron-deficient phosphite ligands is important to suppress dimerization of the terminal alkynes to enynes.     

Synthesis of polycyclic spiro-fused indolines via IBX-mediated cascade cyclization

We report a 2-iodoxybenzoic acid (IBX)-mediated intarmolecular oxidative spiro-fused tandem cyclization reaction of tryptophan analogs bearing an N-arylamides side-chain to rapidly afford polycyclic spiroindolines featuring multiple stereocenters including a quaternary stereocenters under mild reaction conditions. Among them, a novelty azaphosphol idine-containing spiroindoline compound is synthesized for the first time. It may open the door to azaphos pholidine-containing spiroindoline compound of potential interest in synthetic and medicinal chemistry. A plausible mechanism is proposed.     

Synthesis of fused polycyclic nitrogen-containing heterocycles via cascade cyclization

A novel strategy for the synthesis of fused polycyclic-nitrogen containing heterocycles via cascade cyclization is described. The methodology involves condensation of 1-(2-aminophenyl)-9H-β-carboline-3-carboxylic acid amide with isothiocyanates followed by in situ treatment of the resulting thioureas with HgCl₂ for 1 h at rt. The one-pot cascade cyclization leads to interesting changes in molecular structure and an increase in molecular complexity. A mechanistic rationale for the cascade cyclization is discussed.     

Synthesis of indoles via palladium-catalyzed C-H activation of N-aryl amides followed by coupling with alkynes

A convenient and efficient method for the construction of indole skeleton was developed via Pd-catalyzed C-H activation of N-aryl amides and subsequent coupling with alkynes. Both stoichiometric and catalytic versions have been successfully achieved.     

Silver-mediated C-H activation: oxidative coupling/cyclization of N-arylimines and alkynes for the synthesis of quinolines

A silver-mediated tandem protocol for the synthesis of quinolines involving the oxidative coupling/cyclization of N-arylimines and alkynes has been developed. We demonstrated that scenario-dependent metalation could occur either at the ortho C-H bond of an N-arylimine through protonation-driven enhancement of acidity or at the terminal C-H bond of an alkyne by virtue of the carbophilic π-acidity of silver. The diverse set of mechanistic manifolds implemented with a single type of experimental protocol points toward the importance of stringent reactivity analysis of each individual potentially reactive molecular site. Importantly, the direct arene C-H bond activation provides a unique and distinct mechanistic handle for the expansion of reactivity paradigms for silver. As expected, the protocol allows for the incorporation of both internal and terminal alkynes into the products, and in addition, both electron-withdrawing and -donating groups are tolerated on N-arylimines, thus enabling the vast expansion of substituent architectures on quinoline framework. Further, an intriguing phenomenon of structural isomerization and chemical bond cleavage has been observed for aliphatic internal alkynes.