Annulation Pathway Research Articles

Tandem Knoevenagel‐Aldol Cyclization Towards Di and Trisubstituted Pyridines: Use of Malonaldehyde and Diethyl Malonate for the Synthesis of Indolizine

AbstractAn effective method for the construction of a multi‐functionalized pyridine motif of indolizine using the [4+2] annulation pathway involves tandem Knoevenagel‐aldol cyclization as a critical step in the process. The production of an indolizine scaffold with a hydroxy group at the C6 position and an ethyl ester/aldehyde group at the C7 position was successfully accomplished using this approach with an excellent yield, with the use of a reagent that contains active methylene and operates under mild conditions. This straightforward and simple protocol allows extensions of the core moiety in a quick and dependable manner.

Facile synthesis of spiro-heterocycles through one-pot multicomponent [3 + 3] cross 1,3-dipolar cycloaddition reactions

A three-component 1,3-dipolar cycloaddition reaction involving ninhydrin, proline, and nitrile imines, which are generated in situ from hydrazonoyl chlorides, has been developed. This transformation can be conceptualized as a cross-1,3-dipolar cycloaddition reaction between two distinct ylides, proceeding via a [3 + 3] annulation pathway. This approach offers a swift route to a diverse array of novel and structurally intricate spiro-multiheterocyclic skeletons, achieving good yields ranging from 80 % to 94 %. Furthermore, the chemical structure of a representative product has been rigorously confirmed via X-ray diffraction analysis.

Tandem Electrochemical Oxidation of Polycyclic Aromatic Amines Towards Carbazoles and Phenazine-based Aza-helicenes.

Experimental and theoretical study of the regioselectivity and mechanism of polycyclic aromatic amine (PAA) electrochemical oxidation is important for designing nitrogen doped large π-conjugated functional molecules. Herein, we used binary-, ternary-, and quaternary-fused PAAs as electro-oxidative reaction substrates to investigate the yield changes of carbazole and phenazine based aza-helicene other than oligomers, which were obtained through pyrrole and pyrazine annulation pathways. Combined with the restrained electrostatic potential (RESP) and steric hindrance factor analysis of the substrate, the electron spin density distribution of free radical resonance hybrid and the spin population analysis of the atoms in the structure of each free radical tautomer indicate that the degree of delocalized dispersion of N free radical and the resulting change in the spin density distribution of C free radical tautomers determine the reaction regioselectivity. The potential charge of the K-region, Bay-region, and L-region adjacent to the C(α)-C(β1) bond is higher than that of other regions within the molecule, and the charge in these high RESP regions tends to delocalize more strongly toward electron-deficient N free radicals. Thus, the activity of N-C(α)-C(β1) region is increased, which supports the proposed free radical addition and free radical coupling mechanism for the electro-oxidative reaction of PAA.

K2CO3-mediated annulation of 1,3-acetonedicarboxylates with 2-fluoro-1-nitroarenes: synthesis of indoles.

The K2CO3-mediated one-pot reaction of 1,3-acetonedicarboxylates with 2 equiv. of substituted 2-fluoro-1-nitrobenzenes has been developed to synthesize various 2,3-dicarboxylate indoles via a tandem annulation pathway. In the effective reaction, one carbon-carbon double bond, one carbon-carbon single bond and one carbon-nitrogen single bond are formed under open-vessel conditions. DFT calculations are used to rationalize the plausible mechanisms.

Substrate‐ and Catalyst‐Controlled C−H Bond Activation/Annulation for Construction of Pyrido[2,3,4‐de]quinazolinones and Indolo[1,2‐c]quinazolinones

AbstractA substrate and catalyst‐controlled synthetic strategy was employed to construct two distinct types of fused polycyclic heterocycles, namely pyrido[2,3,4‐de]quinazolinones and indolo[1,2‐c]quinazolinones. The most notable advantage of this method is its ability to rapidly generate two different polycyclic scaffolds via a simple C−H activation and subsequent cyclization cascade pathway. Specifically, sulfoxonium ylides played a crucial role in both transformations, serving as a two‐carbon synthon and a one‐carbon synthon, to independently construct the two fused polycyclic scaffolds through [4+2] and [4+1] annulation pathways, respectively.

Computational Study on Ni−Al Bimetal‐Catalyzed Twofold C−H Annulation Reaction: Mechanism, Origin of Selectivity, and Role of SPO Ligand

AbstractDensity functional theory calculations have been performed to probe the reaction mechanism of the recently reported twofold C−H annulation of arylformamides with alkynes by Ni−Al bimetallic catalysis. The main pathway consisted of the formyl C−H activation, phenyl C−H activation, migratory insertion, and reductive elimination steps in succession. The desired annulation product was found to be the equilibrium‐controlled product, while the minor hydrocarbamoylation product was the kinetics‐controlled product. Calculated free‐energy profiles indicated that the annulation and hydrocarbamoylation pathways could intersect with each other and merge into a mechanism unity, in which the reaction system entered the hydrocarbamoylation pathway in early stage and switched to the annulation pathway afterwards via suitable transition states. The modified mechanism picture demonstrated the phenyl C−H activation step to be the rate‐determining step with a free‐energy barrier of 27.7 kcal/mol. However, this barrier was only 19.4 kcal/mol on the basis of a single annulation pathway, which could not satisfactorily agree with the experimental conditions and kinetic isotope effects. In addition, the crucial role of the bifunctional secondary phosphine oxide ligand in promoting the reactivity and selectivity was elucidated in detail.

Synthesis of N-functionalized 2,3-disubstituted benzofurans/naphthofurans from para-quinone methides and isocyanides via the [4 + 1] annulation pathway

Synthesis of 2-amino substituted benzo- and naphtho-furans via [4 + 1] cycloaddition of 2-hydroxy-substituted p-QMs and various alkyl/aryl isocyanides has been achieved by using Sc(OTf)3 as the catalyst.

Ru(II)-Catalyzed C–H Activation and Alkyne Annulation Reaction of Phenyl Indandiones: Synthesis of Spirobi[indene]diones

AbstractA Ru(II)-catalyzed synthesis of spirobi[indene]dione from phenyl indandione and alkyne is reported. This metal-catalyzed cyclization reaction proceeds through hydroxy group directed C(sp2)–H bond activation, keto–enol tautomerization and alkyne annulation pathways.

An approach for the synthesis of 2-aryl-3-sulfonyl substituted quinolines through an electrochemical cascade annulation pathway

An electrochemical protocol for the synthesis of 2,3-disubstituted quinolines by reacting benzoxazinones with arylsulfonyl hydrazides was established under simple and mild conditions (room temperature and an undivided cell).

Synthesis of 5H-Chromeno[2,3-d]pyrimidin-5-one Derivatives via Microwave-Promoted Multicomponent Reaction.

A microwave-promoted multicomponent reaction of 3-formylchromones, amines, and paraformaldehyde was achieved under catalyst-free and solvent-free conditions, delivering 5H-chromeno[2,3-d]pyrimidin-5-one derivatives in good to excellent yields via an unexpected annulation pathway, which further expanded the synthetic application of paraformaldehyde as a C1 building block.

Is the metal involved or not? A computational study of Cu(I)-catalyzed [4 + 1] annulation of vinyl indole and carbene precursor

The Cu(I)-catalyzed [4 + 1] annulation of vinyl indoles and a carbene precursor is a powerful method for constructing cyclopentaindole derivatives. Density functional theory (DFT) calculations were used to elucidate the mechanism and regioselectivity of this reaction. After Cu-assisted indole C3-alkylation, direct 1,5-annulation was favored over the Cu-assisted annulation pathway. Furthermore, the regioselectivity for 1,5-annulation was attributed to the generated five-membered-ring product being more stable than the three-membered-ring product from 1,3-annulation, which was the kinetically favored pathway.

Mechanism and regio- and stereoselectivity in an NHC-catalyzed Mannich/lactamization domino reaction.

Density functional theory (DFT) calculations (M06-2X) have been employed to disclose the mechanisms and regio- and stereo-selectivities of the N-heterocyclic carbene (NHC)-catalyzed reaction of 2-benzothiazolimines and α-chloroaldehydes. The preferred mechanism is initiated by the nucleophilic attack of NHC on α-chloroaldehyde (first step), followed by 1,2-proton transfer which was assisted by the Brønsted acid DABCO·H+ to generate the Breslow intermediate (second step). The cleavage of the C-Cl bond (third step) and deprotonation (fourth step) form the enolate intermediate. This further reacts with 2-benzothiazolimine which leads to the formation of a new C-C bond (fifth step). Subsequent cyclization takes place via the formation of a new C-N bond (sixth step). Catalyst regeneration completes the whole catalytic cycle and affords the final product (seventh step). The DFT results indicate that the fifth step determines the stereochemistry of the reaction and leads to benzothiazolopyrimidinone with the SS configuration, which agrees well with experimental observations. Intramolecular cyclization is found to be the regioselectivity-determining step, for which the [4+2] annulation pathway is more preferred than that via [2+2] annulation, which again agrees well with experimental observations. Based on the mechanism proposed, the origins of regio- and stereoselectivities have also been investigated by performing distortion/interaction, natural bond orbital (NBO) and non-covalent interaction (NCI) analyses. The mechanistic insights gained in this work should be helpful in the rational design of potential catalysts for analogous reactions.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-Mediated Tandem Oxidative-Coupling/Annulation of o-Hydroxyaryl Enaminones with Cycloheptatriene

AbstractA DDQ-mediated tandem reaction of easily available o-hydroxy­aryl enaminones and cycloheptatriene is disclosed. It provides an effective and convenient method for the synthesis of 3-(cycloheptatrienyl)-substituted chromones in moderate to excellent yields with good functional group tolerance; this reaction involves an oxidative coupling and intramolecular annulation pathway.

A ZnI2-catalyzed regioselective cascade 1,4-conjugate addition/5-exo-dig annulation pathway for one-pot access to heterobiaryl frameworks.

Facile access to π-extended heterobiaryl compounds via a non-cross-coupling strategy has been achieved. In the presence of an inexpensive ZnI2 catalyst and versatile propargylamine and β-naphthol (or β-naphthylamine and β-naphthyl mercaptan) starting materials, a variety of sterically hindered heterobiaryl frameworks can be easily obtained. The present catalytic system offers excellent selectivity, good-to-excellent product yields, and good functional group tolerance including, for instance, -CN, -COOH, -C(O)R, -Br and -Cl groups. This cyclization process is proposed to proceed via in situ generated alkynyl o-quinone methides (o-AQMs), following a cascade intermolecular 1,4-conjugate addition/5-exo-dig annulation/1,3-H shift pathway.

Cp*CoIII-Catalyzed C-H Alkenylation/Annulation Reactions of Indoles with Alkynes: A DFT Study.

The Cp*CoIII-catalyzed C-H functionalization reaction of indoles with alkynes was examined using M06-level DFT calculations. The C≡C bond in the alkyne was inserted into the Co-C bond of an intermediate alkenyl-Co complex given by the acetate-assisted C-H bond activation step. Then the reaction pathway bifurcated into alkenylation and annulation pathways. In the case where AcOH, which was eliminated by ligand exchange for the alkyne, recoordinated to the Co atom, alkenylation proceeded via proton transfer. On the other hand, the annulation pathway to give pyrroloindolone became significant in the case where the ring-closure C-C bond formation was followed by the attachment of AcOH. At a high temperature (393 K), the difference in the Gibbs free energy between the transition state for proton transfer in the alkenylation pathway and that for the ring-closure C-C bond formation in the annulation pathway was relatively small, so both reactions could proceed. In addition, we also found another pathway to provide the directing-group migration on the way to annulation. This finding well elucidates the recent experimental report that tetrasubstituted alkenes were obtained as the major product under different conditions.

Diverting C–H Annulation Pathways: Nickel-Catalyzed Dehydrogenative Homologation of Aromatic Amides

Direct homologation of aromatic amides with internal alkynes has been accomplished via a nickel-catalyzed sequential C–H activation reaction. The use of a rigid chelating group and a strong aprotic polar solvent successfully divert the classical [4 + 2] annulation to the [2 + 2 + 2] homologation pathway. This transformation is promoted by a simple nickel catalyst without the need of stoichiometric metal oxidants. Mechanistic studies support an unusual substrate-assisted ligand exchange process. NMR and X-ray data suggest a [5,5] Ni-bridged metallacycle as the catalyst resting state. Substrate assisted directing group swap plays an important role for the subsequent meta-C-H insertion. In contrast, [4 + 2] annulation can be accomplished using a bulky, electron-rich phosphine ligand, which favors rapid reductive C–N elimination.

Enantioselective [4 + 1] Annulation Reactions of α-Substituted Ammonium Ylides To Construct Spirocyclic Oxindoles.

Ammonium ylides have a long history in organic synthesis, but their application in asymmetric catalysis is still underdeveloped in regard to both substrate scope and reaction pathways compared with phosphorus and sulfur ylides. Here a previously unreported asymmetric [4 + 1] annulation reaction of 3-bromooxindoles and electron-deficient 1-azadienes has been developed through ammonium ylide catalysis of a newly designed 2'-methyl α-isocupreine (α-MeIC), efficiently delivering spirocyclic oxindole compounds incorporating a dihydropyrrole motif in excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this work represents the first example of asymmetric catalysis of ammonium ylides bearing α-substitutions, and the catalytic [4 + 1] annulation pathway of ammonium ylides is also unprecedented. Moreover, (1)H NMR, mass spectroscopy, and computational calculation studies were conducted, and the catalytic cycle and a tentative explanation of the enantioselective mechanism have been successfully elucidated.

ChemInform Abstract: Ruthenium(II)‐Catalyzed N‐Substituted Phthalimide Synthesis via C—H Activation/[3 + 2] Annulation.

Abstract Ruthenium-catalyzed intermolecular [3 + 2] annulation pathway for aromatic acids with isocyanates to afford N-substituted phthalimide in one step is demonstrated, which provides an efficient process to direct preparation of phthalimide from commercially available starting materials and environmentally benign catalysts. This cascade cyclization involves the direct functionalization of an ortho C–H bond and the subsequent intramolecular nucleophilic substitution. There is no theoretical waste except for water generated in the reaction.

Synthesis of oxaspiranic compounds through [3 + 2] annulation of cyclopropenones and donor–acceptor cyclopropanes.

The Sc(OTf)3-catalyzed [3 + 2]-annulation reaction between cyclopropenones and donor–acceptor cyclopropanes is described. The process leads directly to the formation of 4-oxaspiro[2.4]hept-1-ene derivatives in good to excellent reaction yields. Density functional theory calculations suggest that the [3 + 2]-annulation pathway is strongly preferred over the possible [3 + 3]-process.

Ruthenium(II)-catalyzed N-substituted phthalimide synthesis via C–H activation/[3+2] annulation

Ruthenium-catalyzed intermolecular [3 + 2] annulation pathway for aromatic acids with isocyanates to afford N-substituted phthalimide in one step is demonstrated, which provides an efficient process to direct preparation of phthalimide from commercially available starting materials and environmentally benign catalysts. This cascade cyclization involves the direct functionalization of an ortho C–H bond and the subsequent intramolecular nucleophilic substitution. There is no theoretical waste except for water generated in the reaction.