Expeditious Synthesis of Spiroindoline Derivatives via Tandem C(sp2)-H and C(sp3)-H Bond Functionalization of N-Methyl-N-nitrosoanilines.

Presented herein is a novel synthesis of pharmaceutically privileged spiroindoline derivatives via cascade reactions of N-methyl-N-nitrosoanilines with diazo homophthalimides. A group of mechanistic studies disclosed that the formation of product involves an unusual reaction mode of N-methyl-N-nitrosoaniline featuring an initial C(sp2)-H bond activation/alkylation followed by a C(sp3)-H bond activation/spiroannulation. To our knowledge, this is the first example in which N-methyl-N-nitrosoaniline acts as a C3N1 synthon to accomplish formal [4+1] spiroannulation with the participation of the N-methyl unit rather than the previously reported C2N1 synthon to undergo formal [3+2] annulation without the participation of the N-methyl unit. In general, this newly developed synthetic protocol features simple and readily accessible starting materials, valuable products, unique reaction mechanism, high efficiency and atom-economy, excellent compatibility with diverse functional groups, and ready scalability.

Synthesis of Acyl Cyclopentaquinolinones through Simultaneous Construction of the Heterocyclic Scaffold and Introduction of the Acyl Group.

Presented herein is an effective and concise synthesis of acyl cyclopentaquinolinone derivatives via the cascade reactions of N-(o-ethynylaryl)acrylamides with α-diazo carbonyl compounds. The formation of product involves a visible light-induced radical formation from α-diazo carbonyl compound followed by its addition onto the acrylamide moiety to trigger double radical annulation, single-electron oxidation, and ß-elimination. To our knowledge, this is the first example in which the cyclopentaquinolinone scaffold was constructed along with the introduction of an acyl group under visible light irradiation conditions. Compared with literature methods for similar purpose, this newly developed protocol has advantages such as readily accessible substrates, mild reaction conditions, valuable products, concise synthetic procedure, and high sustainability. With all these merits, this method is expected to find wide applications in the construction of related acyl heterocyclic skeletons.

C-H activation-initiated spiroannulation reactions and their applications in the synthesis of spirocyclic compounds.

Spirocyclic skeletons are prevalent in natural products, pharmaceuticals and organic functional materials. Meanwhile, transition-metal-catalyzed C-H activation reactions have demonstrated unparalleled advantages such as high efficiency, excellent atom-economy, good chemoselectivity and regioselectivity for the formation of target organic molecules. In recent years, C-H activation reactions have been creatively utilized in the synthesis of spirocyclic compounds. This review summarizes the most recent progress made in C-H activation-initiated spiroannulation reactions and their applications in the construction of structurally diverse and biologically valuable spirocyclic scaffolds by using alkynes, diazo compounds, maleimides, alkenes, quinones and cyclopropenones as the coupling partners.

Synthesis of Naphtho[1',2':4,5]furo[3,2-b]pyridinones via Ir(III)-Catalyzed C6/C5 Dual C-H Functionalization of N-Pyridyl-2-pyridones with Diazonaphthalen-2(1H)-ones.

Presented herein is an unprecedented synthesis of naphtho[1',2':4,5]furo[3,2-b]pyridinones via Ir(III)-catalyzed C6/C5 dual C-H functionalization of N-pyridyl-2-pyridones with diazonaphthalen-2(1H)-ones. This protocol forms C-C and C-O bonds in one pot in which diazonaphthalen-2(1H)-ones serve as bifunctional reagents, providing both alkyl and aryloxy sources. To the best of our knowledge, this is the first example of an Ir(III)-catalyzed synthesis of the title compounds by using diazonaphthalen-2(1H)-ones as bifunctional substrates. Notably, this method features operational simplicity, good functional group tolerance, high efficiency, and high atom economy.

Synthesis of 1,7-Fused Indolines Tethered with Spiroindolinone Based on C-H Activation Strategy with Air as a Sustainable Oxidant.

Herein, we present an efficient synthesis of 1,7-fused indolines tethered with a spiroindolinonyl moiety through the cascade reaction of indolin-1-yl(aryl)methanimines with diazo oxindoles. To the best of our knowledge, this is the first example in which 1,7-fused indoline skeleton was constructed along with the simultaneous introduction of a spiro element initiated by the C-H bond activation of indoline. In forming the title product, the indoline substrate and the diazo coupling partner demonstrated an unprecedented reaction pattern in which the latter acts as a C1 synthon to participate in the construction of the spirocyclic scaffold through the reductive elimination of a key seven-membered Ru(II) species by using air as an effective and sustainable oxidant to regenerate the active catalyst. Moreover, studies on the cytotoxicity of selected products against several human cancer cell lines demonstrated their potential as lead compounds for the development of anticancer drugs. With notable features such as simple and economical substrates, pharmaceutically valuable products with sophisticated spirocyclic skeleton, mild reaction conditions, cost-free and sustainable oxidants, high efficiency, excellent compatibility with diverse functional groups, and scalability, this method is expected to find wide applications in related areas.

Synthesis of O-Heterocycle Spiro-Fused Cyclopentaquinolinones and Cyclopentaindenes through Visible Light-Induced Radical Cyclization Reactions.

Presented herein is an effective and sustainable synthesis of O-heterocycle spiro-fused cyclopentaquinolinone and cyclopentaindene derivatives through light-driven cascade reactions of N-(o-ethynylaryl)acrylamides or 2-(2-(phenylethynyl)benzyl)acrylate with various O-heterocycles. Experimental mechanistic studies revealed that these reactions are initiated by visible light-induced radical formation from O-heterocycle and its regioselective addition onto the acrylamide or acrylate moiety followed by 6-exo-dig and 5-endo-trig cascade radical annulation, which is terminated by single electron oxidation and proton elimination. Compared with previously reported synthetic methods for similar purposes, this newly developed protocol has advantages such as a broad substrate scope, extremely mild reaction conditions, excellent atom-economy, high efficiency, and good compatibility with diverse functional groups. With all of these merits, this method is expected to find wide applications in the related research arena.

Condition-Controlled Selective Synthesis of Pyranone-Tethered Indazoles or Carbazoles through the Cascade Reactions of N-Nitrosoanilines with Iodonium Ylides.

Presented herein is a condition-controlled selective synthesis of pyranone-tethered indazoles or carbazole derivatives via the cascade reactions of N-nitrosoanilines with iodonium ylides. Mechanistically, the formation of the former involves an unprecedented cascade process including nitroso group-directed C(sp2)-H bond alkylation of N-nitrosoaniline with iodonium ylide followed by intramolecular C-nucleophilic addition to the nitroso moiety, solvent-assisted cyclohexanedione ring opening, and intramolecular transesterification/annulation. On the contrary, the formation of the latter involves the initial alkylation followed by intramolecular annulation and denitrosation. These developed protocols feature easily controllable selectivity, mild reaction conditions, a clean and sustainable oxidant (air), and valuable products that are structurally diverse. In addition, the utility of the products was showcased by their facile and diverse transformations into synthetically and biologically interesting compounds.

Synthesis of Pyrazolidinone-Fused Benzotriazines through C-H/N-H Bond Functionalization of 1-Phenylpyrazolidinones with Oxadiazolones.

Presented herein is an efficient synthesis of pyrazolidinone-fused benzotriazines through the cascade reaction of 1-phenylpyrazolidinones with oxadiazolones. The formation of the title products is initiated by Rh(III)-catalyzed C-H/N-H bond metallation of 1-phenylpyrazolidinone and subsequent coordination with oxadiazolone followed by migratory insertion along with CO2 liberation, proto-demetallation, and intramolecular condensation. To our knowledge, this is the first synthesis of pyrazolidinone-fused benzotriazines based on the C-H bond activation strategy by using oxadiazolone as an easy-to-handle amidine surrogate. In general, this new protocol has advantages such as valuable products, easily accessible substrates, redox neutral conditions, concise synthetic procedure, high efficiency, and compatibility with diverse functional groups. Moreover, the usefulness of this method is further showcased by scale-up synthetic scenario and suitability to substrates derived from natural products such as thymol and nerol.

Oxoammonium salt-promoted diverse functionalization of saturated cyclic amines with dinucleophiles.

Oxoammonium salt-promoted diverse functionalization of saturated cyclic amines with different dinucleophiles under mild conditions is presented. Specifically, when thiocyanate is used as a 1,3-dinucleophile, hexahydrothiazolo[4,5-b]pyridin-2(3H)-one derivatives are formed via the formation of the ß-TEMPO-tethered cyclic iminium ion as a key intermediate. By contrast, when benzene-1,2-diamine is used as a 1,4-dinucleophile, 2-alkylquinoxaline derivatives are afforded via generation of the ß-oxo cyclic iminium ion as a key intermediate. In addition, the usefulness of 2-alkylquinoxalines is showcased through their facile conversion into N-(2-oxo-2-(quinoxalin-2-yl)ethyl)nitrous amides featuring the synthetically useful N-NO moiety and the carbonyl group.

Rh(III)-Catalyzed Spiroannulation Reaction of N-Aryl Nitrones with 2-Diazo-1,3-indandiones: Synthesis of Spirocyclic Indole-N-oxides and Their 1,3-Dipolar Cycloaddition with Maleimides.

An efficient strategy for the preparation of spirocyclic indole-N-oxide compounds through a Rh(III)-catalyzed [4 + 1] spiroannulation reaction of N-aryl nitrones with 2-diazo-1,3-indandiones as C1 synthons under extremely mild conditions is presented. From this reaction, 40 spirocyclic indole-N-oxides were easily obtained in up to 98% yield. In addition, the title compounds could be successfully used for the construction of structurally intriguing maleimide-containing fused polycyclic scaffolds via a diastereoselective 1,3-dipolar cycloaddition reaction with maleimides.

t-BuOK-Catalyzed Regio- and Stereoselective Intramolecular Hydroamination Reaction Leading to Phthalazinoquinazolinone Derivatives.

We report herein an efficient and practical strategy for the preparation of 5H-phthalazino[1,2-b]quinazolin-8(6H)-one derivatives through a t-BuOK-catalyzed intramolecular hydroamination reaction of functionalized quinazolinones under extremely mild reaction conditions. A variety of quinazolinone substrates are well tolerated to furnish the corresponding products in good to high yields via an exclusive 6-exo-dig cyclization process. The present protocol has the advantages of readily obtainable starting materials, broad substrate scope, and high regio- and stereoselectivity.

Solvent-Dependent Selective Synthesis of CF3-Tethered Indazole Derivatives Based on Multiple Bond Activations.

Presented herein is a solvent-dependent selective synthesis of CF3-tethered indazole derivatives via the cascade reactions of 1-arylpyrazolidinones with trifluoromethyl ynones. Mechanistically, the formation of the title products involves cascade N-H/C-H/C-N/C-C bond cleavage along with pyrazole ring formation and pyrazolidinone ring opening. For the formation of a pyrazole scaffold, 1-phenylpyrazolidinone acts as a C2N2 synthon, while trifluoromethyl ynone serves as a C1 synthon. Meanwhile, trifluoromethyl ynone also acts as an enol unit to facilitate the ring opening of the pyrazolidinone ring and provide a trifluoropropenoxy fragment via cleavage of the alkynyl triple bond and migration of the cleaved moiety. When the reaction was run in trifluoroethanol instead of DCE, it selectively afforded indazole derivatives tethered with a trifluoroethoxy moiety through in situ transesterification. To our knowledge, this is the first synthesis of CF3-tethered indazole derivatives via concurrent alkynyl activation, pyrazole formation, and CF3 migration.

Selective Construction of Spiro or Fused Heterocyclic Scaffolds via One-pot Cascade Reactions of 1-Arylpyrazolidinones with Maleimides.

Presented herein is a controllable selective construction of spiro or fused heterocyclic scaffolds through the one-pot cascade reactions of 1-phenylpyrazolidinones with maleimides. To be specific, succinimide spiro pyrazolo[1,2-a]pyrazolones were effectively formed via [4 + 1] spiroannulation of 1-phenylpyrazolidinones with maleimides through simultaneous C(sp2)-H bond activation/functionalization and intramolecular cyclization along with the traceless fusion of the pyrazolidinonyl unit into the final product. In this reaction, air acts as a cost-effective and environmentally sustainable oxidant to assist the regeneration of the Rh(III) catalyst. Alternatively, succinimide-fused pyrazolidinonylcinnolines were formed from the same starting materials through an initial [4 + 1] spiroannulation followed by base-promoted skeleton rearrangement of the in situ formed spiro product without isolation. Notable features of these protocols include easily tunable selectivity, broad substrate scope, cost-effective and sustainable oxidant, excellent atom economy, and facile scalability.

Selective Synthesis of Pyrazolonyl Spirodihydroquinolines or Pyrazolonyl Spiroindolines under Aerobic or Anaerobic Conditions.

Presented herein is a condition-controlled selective synthesis of pyrazolonyl spirodihydroquinolines or pyrazolonyl spiroindolines through formal [5 + 1] or [4 + 1] spiroannulation of 2-alkenylanilines with diazopyrazolones. Mechanistically, the formation of the title products involves initial generation of a pyrazolonyl spiro-fused seven-membered ruthenacycle species serving as a key intermediate through Ru(II)-catalyzed C-H/N-H bonds metalation, carbene formation, and its migratory insertion. When the reaction is carried out under air, the key intermediate undergoes reductive elimination to afford spirodihydroquinoline. When the reaction is run under argon, the key intermediate undergoes protonation and intramolecular nucleophilic addition to furnish spiroindoline. This work provides an atom-economical protocol for the effective functionalization of alkenyl C(sp2)-H bond, allowing rapid and selective assembly of valuable spiroscaffolds with a broad range of substrates.

B(C6F5)3-Catalyzed α,ß-Difunctionalization and C-N Bond Cleavage of Saturated Amines with Benzo[c]isoxazoles: Access to Quinoline Derivatives.

Herein, we disclose a strategy to realize α,ß-difunctionalization and C-N bond cleavage of saturated amines with benzo[c]isoxazoles via a B(C6F5)3-catalyzed consecutive hydrogen-borrowing and [4 + 2] cycloaddition followed by a C-N bond cleavage process. In general, the reactions proceed efficiently in the absence of any oxidant and metal catalyst to afford a broad range of quinoline derivatives starting from easily accessible substrates in an atom-economical manner.

Oxoammonium Salt-Promoted Multifunctionalization of Saturated Cyclic Amines Based On ß-Oxo Cyclic Iminium Ion Intermediates.

Herein we describe a convenient method for multiple C(sp3)-H bond functionalization of saturated cyclic amines through oxoammonium salt-promoted oxidation to afford a ß-oxo cyclic iminium ion as a key intermediate, followed by cascade addition with thiocyanate and diverse N-, O-, and S-containing nucleophiles in the green solvent and EtOH. Notably, chiral spiro azapolyheterocycles were prepared enantioselectively (>20:1 dr, up to 99% ee) when cysteine or serine esters were used as substrates. Moreover, the concise late-stage modification of several natural product derivatives was accomplished using this method.

Concise Synthesis of Spirocyclic Dihydrophthalazines through Spiroannulation Reactions of Aryl Azomethine Imines with Cyclic Diazo Compounds.

Spiroannulation reactions are fundamental and invaluable for the synthesis of spirocyclic compounds. Presented herein are novel cascade reactions of aryl azomethine imines with cyclic diazo compounds leading to the formation of spirocyclic dihydrophthalazine derivatives. Based on experimental mechanistic studies, the formation of the title products is believed to go through azomethine imine-assisted cylcometalation, Rh-carbene formation through dediazonization, and migratory insertion followed by reductive elimination and azomethine imine ring opening. Control experiments revealed that air acts as an effective and sustainable co-oxidant to facilitate the cascade reaction. In general, this concise synthesis of the unprecedented spirocyclic dihydrophthalazine derivatives has advantages such as easily accessible substrates, good functional group compatibility, mild reaction conditions, high efficiency and selectivity, and excellent atom-economy. In addition, the value of this protocol is underlined by its ready scalability and divergent derivation of products.

Condition-Dependent Selective Synthesis of Indolo[1,2-c]quinazolines and Indolo[3,2-c]quinolines from 2-(1H-Indol-2-yl)anilines and Sulfoxonium Ylides.

In this paper, a selective synthesis of indolo[1,2-c]quinazolines and indolo[3,2-c]quinolines through the cascade reactions of 2-(1H-indol-2-yl)anilines with sulfoxonium ylides is presented. The formation of products involves the generation of a carbene species from sulfoxonium ylide and its N-H bond insertion reaction with 2-(1H-indol-2-yl)aniline followed by deoxygenative imine formation, intramolecular N- or C- nucleophilic addition and deoxygenative aromatization. This switchable synthesis was condition-dependent. In the presence of K2CO3 in CH3CN, the reaction mainly furnished indolo[1,2-c]quinazolines. In the presence of HOAc in dioxane, it selectively afforded indolo[3,2-c]quinolines. In addition, direct C-H/N-H functionalization of the products obtained provides a convenient and direct access to polycyclic heteroaromatic compounds. These novel protocols have advantages such as readily accessible substrates, easily tunable selectivity, good compatibility with diverse functional groups, and the use of air as a cost-free and sustainable oxidant.

Synthesis of N-Arylindoles from 2-Alkenylanilines and Diazonaphthalen-2(1H)-ones through Simultaneous Indole Construction and Aryl Introduction.

In this paper, an efficient synthesis of N-arylindoles through the cascade reaction of 2-alkenylanilines with diazonaphthalen-2(1H)-ones is presented. Mechanistically, this reaction involves the generation of a Ru-carbene complex from diazonaphthalen-2(1H)-one, followed by carbene N-H bond insertion with 2-alkenylaniline, intramolecular cyclization, and oxidative aromatization. In this reaction, the Ru(II) complex acts as a multifunctional catalyst to promote not only the carbene formation but also the intramolecular cyclization and the dehydrogenative aromatization. Meanwhile, air acts as a green and cost-effective oxidant. To our knowledge, this is the first example in which N-arylindoles were synthesized through simultaneous introduction of the N-aryl unit and construction of the indole scaffold. Notable advantages of this method include readily accessible and halide-free substrates, additive-free reaction conditions, good efficiency, excellent atom economy, and compatibility with diverse functional groups. In addition, the utility of the product thus obtained was showcased by its diverse structural transformations.

Synthesis of Spiro[benzo[d][1,3]oxazine-4,4'-isoquinoline]s via [4+1+1] Annulation of N-Aryl Amidines with Diazo Homophthalimides and O2.

Synthesis of spiro[benzo[d][1,3]oxazine-4,4'-isoquinoline]s through a unique [4+1+1] annulation of N-aryl amidines with diazo homophthalimides and O2 is presented. This unprecedented spirocyclization reaction features readily obtainable substrates, structurally and pharmaceutically attractive products, a cost-free and clean oxygen source, sustainable reaction medium, tolerance of a broad spectrum of functional groups, and an interesting reaction mechanism based on sequential C(sp2)-H/C(sp3)-H bond cleavage and oxygen insertion.