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.

Synthesis of CF3-Substituted N-Heterocyclic Compounds Based on C-H Activation-Initiated Formal [2 + 3] Annulation Featuring with a Latent Nucleophilic Site.

Presented herein is a novel synthesis of CF3-substituted pyrrolo[1,2-a]indole derivatives based on the cascade reactions of N-alkoxycarbamoyl indoles with CF3-ynones. Mechanistically, the formation of a product involves a tandem process initiated by Rh(III)-catalyzed and N-alkoxycarbamoyl group-directed regioselective C2-H alkenylation of the indole scaffold followed by in situ removal of the directing group and intramolecular N-nucleophilic addition/annulation under one set of reaction conditions. To our knowledge, this is the first example in which a N-alkoxycarbamoyl unit initially acts as a directing group for C2-H functionalization of the indole scaffold and is then removed to provide the required reactive NH-moiety for subsequent intramolecular condensation. Moreover, the products thus obtained could be conveniently transformed into structurally and biologically attractive cycloheptenone fused indole derivatives through an acid-promoted cascade transformation. In addition, studies on the activity of selected products against human cancer cell lines demonstrated their potential as lead compounds for the development of novel anticancer drugs.

Synthesis of CF3-Isoquinolinones and Imidazole-Fused CF3-Isoquinolinones Based on C-H Activation-Initiated Cascade Reactions of 2-Aryloxazolines.

Presented herein are novel syntheses of CF3-isoquinolinones and imidazole fused CF3-isoquinolinones based on the cascade reactions of 2-aryloxazolines with trifluoromethyl imidoyl sulfoxonium ylides. The formation of CF3-isoquinolinone involves an intriguing cascade process including oxazolinyl group-assisted aryl alkylation through C(sp2)-H bond metalation, carbene formation, migratory insertion, and proto-demetalation followed by intramolecular condensation and water-promoted oxazolinyl ring-scission. With this method, the isoquinolinone scaffold tethered with valuable functional groups was effectively constructed. By taking advantage of the functional groups embedded therein, the products thus obtained could be readily transformed into imidazole-fused CF3-isoquinolinones or coupled with some clinical drugs to furnish hybrid compounds with potential applications in drug development. In general, the developed protocols feature expeditious and convenient formation of valuable CF3-heterocyclic skeletons, broad substrate scope, and ready scalability. In addition, studies on the activity of selected products against some human cancer cell lines demonstrated their potential as lead compounds for the development of novel anticancer drugs.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

Selective Synthesis of Dihydrophenanthridine and Phenanthridine Derivatives from the Cascade Reactions of o-Arylanilines with Alkynoates through C-H/N-H/C-C Bond Cleavage.

In this paper, an unprecedented selective synthesis of dihydrophenanthridine and phenanthridine derivatives through the cascade reactions of 2-arylanilines with alkynoates is presented. Mechanistic studies showed that the formation of the dihydrophenanthridine scaffold involves an initial C(sp2)-H alkenylation of 2-arylaniline with alkynoate followed by an intramolecular aza-Michael addition. When this reaction is carried out at elevated temperature, the in situ formed substituted dihydrophenanthridine readily undergoes a retro-Mannich-type reaction to give the corresponding phenanthridine through C-C bond cleavage. Compared with literature methods, this novel protocol has advantages such as easily obtainable substrates with a free amino group, pharmaceutically privileged products, cheap catalysts, and conveniently controllable selectivity.

Direct α-Alkenylation of Cyclic Amines with Maleimides through Fe(III)-Catalyzed C(sp3)-H/C(sp2)-H Cross Dehydrogenative Coupling.

Presented herein is a novel and efficient α-C(sp3)-H alkenylation of cyclic amines with maleimides. Mechanistically, this C(sp3)-H/C(sp2)-H cross dehydrogenative coupling (CDC) reaction involves a cascade procedure including oxidative α-amino radical formation from the cyclic amine substrate and nucleophilic addition of the in situ formed α-amino radical onto the electron-deficient carbon-carbon double bond of maleimide followed by oxidation and ß-elimination. Notably, this direct α-functionalization provides an effective alternative to the conventional ionic reaction mode, in which an imine or iminium intermediate is formed to react with electron-rich coupling partners other than electron-deficient ones. In general, this method features readily available and structurally diverse substrates, a green and economical catalyst, a unique reaction pathway, mild reaction conditions, high efficiency, and excellent atom economy. This new reaction enriches the application of Fe(III)-catalyzed C(sp3)-H activation and functionalization.

Synthesis of Hydroxysuccinimide Substituted Indolin-3-ones via One-Pot Cascade Reaction of o-Alkynylnitrobenzenes with Maleimides under Au(III)-Cu(II) Relay/Synergetic Catalysis.

Presented herein is a one-pot cascade reaction of o-alkynylnitrobenzenes with maleimides leading to the formation of hydroxysuccinimide substituted indolin-3-ones under Au(III)-Cu(II) relay/synergetic catalysis. Mechanistically, the formation of the title products involves an unprecedented cascade process including (1) nitro-alkyne cycloisomerization of o-alkynylnitrobenzene to give isatogen; (2) [3 + 2] dipolar cycloaddition of isatogen with maleimide; and (3) ring opening of the in situ formed isoxazolidine moiety under neutral conditions. Notably, a wide range of substrates bearing various functional groups are compatible with the reaction conditions to give a series of highly valuable hybrid compounds in good efficiency with excellent atom economy. In addition, the products thus obtained could be easily transformed into the corresponding maleimide substituted indolin-3-ones. Importantly, some products demonstrated significant antiproliferative activity in human cancer cell lines.

Synthesis of Dihydroquinolinone Derivatives via the Cascade Reaction of o-Silylaryl Triflates with Pyrazolidinones.

Presented herein is a novel synthesis of dihydroquinolinone derivatives through an unprecedented cascade reaction of o-silylaryl triflates with pyrazolidinones. Mechanistically, the formation of the title products is believed to involve a cascade procedure including in situ formation of aryne and its addition with pyrazolidinone followed by N-N bond cleavage and intramolecular C-C bond formation/annulation. Compared with literature methods for the synthesis of dihydroquinolinones, this protocol has advantages such as multistep transformations accomplished in one pot, broad substrate scope, mild reaction conditions, and good tolerance of diverse functional groups. In addition, the products thus obtained demonstrated significant in vitro antiproliferative activity in selected human cancer cell lines.

Synthesis of Succinimide Spiro-Fused Sultams from the Reaction of N-(Phenylsulfonyl)acetamides with Maleimides via C(sp2)-H Activation.

Presented herein is an effective preparation of succinimide spiro-fused sultams through the coupling reaction of N-(phenylsulfonyl)acetamides with maleimides. It is deduced that this reaction should proceed through a cascade process including Rh(III)-catalyzed C(sp2)-H bond cleavage of N-(phenylsulfonyl)acetamide, maleimide double bond insertion into the C-Rh bond, ß-hydride elimination, reductive elimination, and intramolecular aza-Michael addition. Notably, this cascade procedure features simultaneous annulation and spirocyclization through traceless fusion of the directing group into target product by using air as an economical oxidant to assist the regeneration of the active Rh(III) catalyst. This new method has several advantages including readily accessible starting materials with broad scope, significantly reduced synthetic steps, redox-neutral conditions, high atom-economy, and sustainability.

Synthesis of ß-Methylsulfonylated N-Heterocycles from Saturated Cyclic Amines with the Insertion of Sulfur Dioxide.

An efficient synthesis of ß-methylsulfonylated N-heterocycles via FeCl3-catalyzed C(sp3)-H dehydrogenation and C(sp2)-H methylsulfonylation of inactivated cyclic amines with the promotion and participation of inorganic sodium metabisulfite and dicumyl peroxide (DCP) has been developed. Notably, bifunctional DCP acted not only as an oxidant to promote the dehydrogenation but also as a methyl radical to participate in the sulfone formation. With this protocol, a number of ß-methylsulfonylated tetrahydropyridines, tetrahydroazepines, and pyrroles were obtained in a facile one-pot manner.