Copper-Catalyzed Intermolecular Alkynylation and Allylation of Unactivated C(sp3)-H Bonds via Hydrogen Atom Transfer.

We describe Cu-catalyzed intermolecular alkynylation and allylation of unactivated C(sp3)-H bonds with singly occupied molecular orbital-philes (SOMO-philes) via hydrogen atom transfer (HAT). Employing N-fluoro-sulfonamide as a HAT reagent, a set of substituted alkene and alkyne compounds were synthesized in high yields with good regioselectivity and functional-group compatibility. Late-stage functionalization of natural products and drug molecules is also demonstrated.

Photoinduced Copper-Catalyzed Site-Selective C(sp2)-C(sp) Cross-Coupling via Aryl Sulfonium Salts.

The classical Sonogashira reaction of aryl electrophiles in the presence of Pd catalysts has been well established as a potent method for arylalkyne synthesis. However, the site-selective C(sp2)-C(sp) cross-coupling strategy using a non-noble-metal catalyst is rare. An efficient alternative approach for the synthesis of arylalkynes via a Cu-catalyzed Sonogashira-type reaction promoted by visible light is described. This method enables site-selective alkynylation from aryl sulfonium salts derived from diverse arenes to a set of arylalkynes with high selectivity and high functional-group compatibility. Moreover, rapid alkynylation of drug molecules is demonstrated.

Facile synthesis of chiral [2,3]-fused hydrobenzofuran via asymmetric Cu(i)-catalyzed dearomative 1,3-dipolar cycloaddition.

Intermolecular asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans with azomethine ylides was enabled by using a chiral Cu(i)/(S,Sp)-iPr-Phosferrox catalyst. As a result, a series of highly stereoselective chiral [2,3]-fused hydrobenzofurans possessing four contiguous stereogenic centers were obtained with good to high yields, diastereoselectivities and enantioselectivities. The reaction has broad substrate scope tolerating various functional groups.

Synthesis of Chiral Six-Membered Carbocyclic Purine Nucleosides via Organocatalytic Enantioselective [3 + 3] Annulation.

A direct route to chiral six-membered carbocyclic purine nucleoside analogues with three chiral stereocenters, including a chiral tetrasubstituted carbon center, via a highly enantioselective [3 + 3] annulation has been established. With the application of Takemoto's catalyst, various chiral six-membered carbocyclic purine nucleoside analogues were obtained in high yields (up to 89%) with moderate to good diastereoselectivities (up to 90:10 dr) and excellent enantioselectivities (92-98% ee). Furthermore, diverse chiral six-membered carbocyclic purine nucleoside analogues were generated by simple transformations.

Visible-Light-Mediated Monoselective Ortho C-H Arylation of 6-Arylpurine Nucleosides with Diazonium Salts.

A combined palladium- and photoredox-catalyzed monoselective arylation of 6-arylpurine nucleosides has been developed by employing purine as a directing group via the photoredox reaction, and many functional groups are well tolerated in this direct C-H arylation condition. Various of functionalized purines (nucleosides) which are potentially of great importance in medicinal chemistry could be obtained under visible light irradiation at room temperature within 4 h.

Enantioselective Intermolecular Cyclopropanations for the Synthesis of Chiral Pyrimidine Carbocyclic Nucleosides.

A direct route to chiral cyclopropylpyrimidine carbocyclic nucleoside analogues has been reported via highly enantioselective intermolecular cyclopropanation reactions of N1-vinylpyrimidines with α-diazoesters. With chiral ruthenium(II)-phenyloxazoline complex (2 mol %) as the catalyst, cyclopropyl pyrimidine nucleoside analogues could be obtained in good yields (71-96% yields) with high levels of diastereo- and enantioselectivities (10:1 to >20:1 dr and 96-99% ee) in 1 min.

Diversity-oriented synthesis of acyclic nucleosides via ring-opening of vinyl cyclopropanes with purines.

The diversity-oriented synthesis of acyclic nucleosides has been achieved via ring-opening of vinyl cyclopropanes with purines. With Pd2(dba)3·CHCl3 as a catalyst, the 1,5-ring-opening reaction proceeded well and afforded N9 adducts as the major form, in which the C=C bonds in the side chain were exclusively E-form. In the presence of AlCl3, the 1,3-ring-opening reaction occurred smoothly, giving N9 adducts as the dominate products. Meanwhile, when MgI2 was used as the catalyst, the 1,3-ring-opening reaction also worked well to form N7 adducts.

Copper-catalyzed intramolecular cyclization of N-propargyl-adenine: synthesis of purine-fused tricyclics.

A novel protocol to construct fluorescent purine-fused tricyclic products via intramolecular cyclization of N-propargyl-adenine has been developed. With CuBr as the catalyst, a series of purine-fused tricyclic products were obtained in good to excellent yields (19 examples, 75-89% yields). When R2 was a hydrogen atom in N-propargyl-adenines, the reactions only afforded the endocyclic double bond products. When R2 was an aryl group, the electron-donating groups favored the endocyclic double bond products, while the electron-withdrawing groups favored the exocyclic double bond products.

A copper-catalyzed domino route toward purine-fused tricyclic derivatives.

Purine-fused tricyclic derivatives have been synthesized via a copper-catalyzed domino Michael/oxidative cross-coupling reaction between adenines and nitroolefins for the first time. With air as the oxidant, this method has high regioselectivity, which provides a new route for constructing purine-nucleoside-conjugated systems with two newly formed C­N bonds. Meanwhile, purine nucleosides with an exocyclic amino group could be obtained easily by simple reduction, which may lead to potential applications in fluorescence recognition of various bases in vivo.

A new strategy to construct acyclic nucleosides via Ag(I)-catalyzed addition of pronucleophiles to 9-allenyl-9H-purines.

A new strategy to construct acyclic nucleosides with diverse side chains was developed. With Ag(I) salts as catalysts, the hydrocarboxylation, hydroamination, and hydrocarbonation reactions proceeded well, affording acyclic nucleosides in good yields (41 examples, 60-98% yields). Meanwhile, these reactions exhibited high chemoselectivities and E-selectivities.

Highly regioselective three-component domino Heck-Negishi coupling reaction for the functionalization of purines at C6.

A highly regioselective three-component domino Heck-Negishi coupling reaction has been developed. Organozinc reagents are used to trap an alkylpalladium intermediate of olefins for a first example in the domino Heck reaction. This reaction is applicable to acrylates (or acrylamides) and purine compounds, producing a series of novel purine compounds with carbon substituents at the C6 position in moderate to good yields.

Radical route for the alkylation of purine nucleosides at C6 via Minisci reaction.

A highly regioselective Minisci reaction with the decarboxylative alkylation of purine nucleosides under mild conditions was developed. With 5 mol % AgNO3 as a catalyst and (NH4)2S2O8 as an oxidant, a series of purine nucleosides including ribosyl, deoxyribosyl, arabinosyl purine nucleosides worked well with primary, secondary, and tertiary aliphatic carboxylic acids.

One-pot synthesis of 7,9-dialkylpurin-8-one analogues: broad substrate scope.

The one-pot and direct synthesis of 7,9-dialkylpurin-8-one analogues with broad substrate scope has been developed. This copper-catalyzed C-H oxidation reaction could avoid multistep synthesis of quaternary ammonium salts and expand the scope of halogenated alkanes. Moreover, benzimidazole derivatives are also applicable in the catalytic system.

Pd(II)-catalyzed one-pot, three-step route for the synthesis of unsymmetrical acridines.

Unsymmetric acridines are synthesized via a one-pot amination/cyclization/aromatization reaction for the first time. With Pd(OAc)2-X-Phos as the catalyst, a series of unsymmetric acridines are obtained in moderate to excellent yields (up to 99% yield). Meanwhile, the diphenylamine intermediate could be isolated, which is evidence of the domino process.

CuI controlled C-C and C-N bond formation of heteroaromatics through C(sp3)-H activation.

A new method for C-C and C-N bond formation of heteroaromatics and C(sp(3))-H alkanes was developed with high regioselectivity. The reaction occurred on C8 to give 8-cylcoakylpurines by C-C bond formation only promoted by tBuOOtBu, while it occurred on the amino group to give N6-alkylated purines by C-N bond formation when 2 equiv of CuI were added. A reaction mechanism was also proposed based on our preliminary experimental data.

Copper-catalyzed synthesis of purine-fused polycyclics.

A novel protocol for a Cu-catalyzed direct C((sp(2)))-H activation/intramolecular amination reaction of 6-anilinopurine nucleosides has been developed. This approach provides a new access to a variety of multiheterocyclic compounds from purine compounds via Cu-catalyzed intramolecular N-H bond tautomerism which are endowed with fluorescence.

Synthesis of fused N-heterocycles via tandem C-H activation.

The synthesis of fused N-heterocycles has been developed using an intramolecular cyclisation of purines or benzimidazoles. A range of medium and large rings were prepared.

Metal catalyzed C(sp3)-H bond amination of 2-alkyl azaarenes with diethyl azodicarboxylate.

Metal-catalyzed direct C(sp(3))-H bond amination of 2-alkyl azaarenes with N=N double bonds has been developed, which expands the scope of C(sp(3))-H bond activation reactions and provides a new access to medicinally important azaarene derivatives.

Nickel catalyzed alkylation of N-aromatic heterocycles with Grignard reagents through direct C-H bond functionalization.

A novel protocol for nickel-catalyzed direct sp(2) C-H bond alkylation of N-aromatic heterocycles has been developed. This new reaction proceeded efficiently at room temperature using a Grignard reagent as the coupling partner. This approach provides new access to a variety of alkylated N-aromatic heterocycles which are potentially of great importance in medicinal chemistry.