Annulation Products Research Articles

Divergent Sc(OTf)3‐Catalyzed Tandem Cyclization of o‐Hydroxyphenyl Enaminones with 1,3,5‐Triazinanes: Access to C3‐Aminomethyl Chromones and Tetrahydropyrimidines

AbstractA Sc(OTf)3‐catalyzed tandem cyclization reaction of o‐hydroxyphenyl enaminones with 1,3,5‐triazinanes has been developed to generate two distinct annulated products in moderate to good yields, which is dominated by the electronic characteristics of the 1,3,5‐triazinanes. The 1,3,5‐triaryl‐1,3,5‐triazinane reacted as C−N synthon to produce C3‐aminomethyl chromone, while the 1,3,5‐trialkyl‐1,3,5‐triazinane acted as C−N−C−N synthons to deliver N,N‐dialkyl tetrahydropyrimidine with a free hydroxyl group.

Catalytic Intermolecular [4+2]-Cycloaddition toward the Stereo­selective C2–C3 Annulation of Indoles

AbstractCatalytic dearomative cycloaddition involving the C2–C3 bond of indoles is a powerful strategy for the synthesis of fused indoline scaffolds. Through dearomative cycloaddition/annulation, planar indole substrates can be readily transformed into rigid, three-dimensional polycyclic complex structures in one step. Molecules with architectural complexity are generally considered to have drug-like properties. Hence, annulation products have tremendous potential for discovering therapeutic properties, and this strategy has become an important part of the medicinal chemistry toolbox. Using appropriate catalyst control, desirable stereoselectivity can be achieved. Previous literature reports reveal that [3+2]-cycloadditions of indoles have been extensively studied. In contrast, the catalytic [4+2]-cycloaddition/dearomatization of indoles has been much less investigated. In this short review, we focus specifically on six-membered ring annulations via [4+2]-cycloaddition with the C2–C3 bond of indoles and discuss the various catalytic methods that have been developed toward this objective.1 Introduction2 [4+2]-Cycloaddition/Annulation of Indoles2.1 Electron-Rich Indoles2.1.1 Transition-Metal Catalysis2.1.2 Organocatalysis2.2 Electron-Deficient Indoles2.2.1 Transition-Metal Catalysis2.2.2 Organocatalysis3 Summary and Outlook

Effect of Solvate Ionic Liquids in the Enantioselective (S)‐Proline‐Catalyzed Mechanochemical Robinson Annulation

AbstractHerein we report our observations from the study of the classical Robinson annulation reaction under solvent‐free mechanochemical activation by means of high‐speed ball milling. In particular, the enantioselective synthesis of the Wieland‐Miescher ketone was used as model reaction. (S)‐Proline was employed as chiral organocatalyst, either alone or in the presence of additives in order to determine their influence on the reaction's speed and stereoselectivity. Most interesting, among the additives that were examined, four solvate ionic liquids (SIL) afforded the desired product with significantly improved enantioselectivity relative to the mechanochemically‐activated reaction catalyzed by (S)‐proline alone. Furthermore, the required reaction time was reduced from 3 days to 90 min. The potential of other proline‐type organocatalysts was explored in this ball‐milling process. Initial attempts to increase the scope of the reaction to afford related annulation products were unsuccessful. HPLC‐MS experiments were carried out in order to detect some of the species that intervene in the mechanism of the (S)‐proline‐catalyzed Robinson cyclization reaction involving 2‐methyl‐1,3‐cyclohexanedione and methyl vinyl ketone.

Computational Insights into Palladium-Catalyzed Site-Selective Anilide and Benzamide-Type [3+2] Annulation via Double C-H Bond Activation.

The mechanism of palladium-catalyzed annulation reactions of benzamide- and anilide-type aromatic systems with maleimides is investigated using density functional theory. Double C-H bond activation is key to forming the desired annulation product. The first C-H bond activation for anilide- and amide-type ligands can occur at the ortho and benzylic C-H bonds, while the second C-H activation occurs at the meta carbon of the aromatic rings. For the anilide-type system, ortho and benzylic C-H bond activations occur via four- and five-membered palladacycles, respectively. In contrast, for the benzamide-type system, ortho and benzylic C-H bond activations occur via five- and six-membered palladacycles, respectively. The energy span model suggests that the initial C-H bond activation step at the benzylic position determines the turnover frequency for both anilide- and benzamide-type systems. Energy decomposition analysis and distortion-interaction/activation-strain analyses are employed to understand the electronic and steric factors controlling the turnover frequency-determining transition state.

Mechanisms, regio- and stereoselectivities involved in NHC[sbnd]catalyzed dearomatizing annulation of ester with ylide: A computational study

The catalytic mechanism for dearomatizing annulation of ester with ylide by a chiral NHC catalyst is investigated by density functional theory (M06–2X) computations. After precatalyst activation giving active NHC, the transformation proceeds via five steps: (1) nucleophilic addition of the NHC to ester, (2) α−CH deprotonation to generate acylazolium intermediate, (3) coupling acylazolium intermediate with ylide to form a new C − C bond, (4) ring closure and (5) elimination of the NHC with formation of the annulation product tricyclic dihydroisoquinoline. The regio- and stereoselectivity controlling step is C − C bond formation. For regioselectivity, local reactivity index analysis indicates that the C1-addition is more favorable than either C3 or C4 addition. The stereoselectivity for the formation of SS-configurational product is ascribed to a number of noncovalent interactions (C–H·O, C–H·N and C–H·π). Electron localization function (ELF) analyses reveal the important role of the NHC in Ccarbonyl−Ocarbonyl bond breaking. These results enable both in-depth understanding of NHC catalysis and rational design of catalytic reactions.

Divergent Synthesis of Multi‐Substituted Aminotetralins via [4+2] Annulation of Aldimines with Alkenes by Rare‐Earth‐Catalyzed Benzylic C(sp3)−H Activation

AbstractThe search for efficient and selective methods for the divergent synthesis of multi‐substituted aminotetralins is of much interest and importance. We report herein for the first time the diastereoselective [4+2] annulation of 2‐methyl aromatic aldimines with alkenes via benzylic C(sp3)−H activation by half‐sandwich rare‐earth catalysts, which constitutes an efficient route for the divergent synthesis of both trans and cis diastereoisomers of multi‐substituted 1‐aminotetralin derivatives from readily accessible aldimines and alkenes. The use of a scandium catalyst bearing a sterically demanding cyclopentadienyl ligand such as C5Me4SiMe3 or C5Me5 exclusively afforded the trans‐selective annulation products in the reaction of aldimines with styrenes and aliphatic alkenes. In contrast, the analogous yttrium catalyst, whose metal ion size is larger than that of scandium, yielded the cis‐selective annulation products. This protocol features 100 % atom‐efficiency, excellent diastereoselectivity, broad substrate scope, and good functional group compatibility. The reaction mechanisms have been elucidated by kinetic isotope effect (KIE) experiments and the isolation and transformations of some key reaction intermediates.

Divergent Synthesis of Multi-Substituted Aminotetralins via [4+2] Annulation of Aldimines with Alkenes by Rare-Earth-Catalyzed Benzylic C(sp3 )-H Activation.

The search for efficient and selective methods for the divergent synthesis of multi-substituted aminotetralins is of much interest and importance. We report herein for the first time the diastereoselective [4+2] annulation of 2-methyl aromatic aldimines with alkenes via benzylic C(sp3 )-H activation by half-sandwich rare-earth catalysts, which constitutes an efficient route for the divergent synthesis of both trans and cis diastereoisomers of multi-substituted 1-aminotetralin derivatives from readily accessible aldimines and alkenes. The use of a scandium catalyst bearing a sterically demanding cyclopentadienyl ligand such as C5 Me4 SiMe3 or C5 Me5 exclusively afforded the trans-selective annulation products in the reaction of aldimines with styrenes and aliphatic alkenes. In contrast, the analogous yttrium catalyst, whose metal ion size is larger than that of scandium, yielded the cis-selective annulation products. This protocol features 100 % atom-efficiency, excellent diastereoselectivity, broad substrate scope, and good functional group compatibility. The reaction mechanisms have been elucidated by kinetic isotope effect (KIE) experiments and the isolation and transformations of some key reaction intermediates.

Metal-free alkyne annulation enabling π-extension of boron-doped polycyclic aromatic hydrocarbons.

A C-H functionalizing annulation reaction of boron-doped polycyclic aromatic hydrocarbons (PAHs) with alkynes is described. This metal-free π-extension provides a new synthetic route to fusion atom B-doped polycyclic aromatic hydrocarbons (PAHs) that is demonstrated with the synthesis of a family of new, functionalized, structurally constrained 6a,15a-diborabenzo[tuv]naphtho[2,1-b]picenes. These annulation products exhibit deep LUMO energy levels, strong visible-range absorptions, and sterically accessible π-systems that can adopt herringbone or π-stacked solid-state structures based on choice of substituents. From regioselectivity and DFT calculations, we propose an annulation mechanism involving intramolecular electrophilic aromatic substitution of a zwitterionic intermediate.

DFT Study on the Mechanism of the Palladium-Catalyzed [3 + 2] Annulation of Aromatic Amides with Maleimides via Benzylic and meta-C-H Bond Activation: Role of the External Ligand Ac-Gly-OH.

The mechanism of the Ac-Gly-OH-assisted palladium-catalyzed [3 + 2] annulation of aromatic amides with maleimides is investigated using density functional theory calculations. The results show that the reaction undergoes the sequential steps of N-H bond deprotonation, first benzylic C-H bond activation, maleimide insertion, second meta-C-H bond activation, reductive elimination, and oxidation. The external ligand Ac-Gly-OH acts as the internal base for hydrogen abstraction in the first benzylic C-H bond activation. The maleimide insertion step is found to be the rate-determining step. Based on the nearly same energetic span of the two pathways to generate the enantio products, the computational results are consistent with the experimental observation that the terminal [3 + 2] annulation products are racemic when using an achiral ligand. These calculation results disclose the detailed reaction mechanism and shed light on some experimental ambiguities.

General Synthesis of N-Alkylindoles from N,N-Dialkylanilines via [4 + 1] Annulative Double C-H Functionalization.

Strategies enabling the construction of indoles and novel polycyclic heterocycles from simple building blocks streamline syntheses in synthetic and medicinal chemistry. Herein, we report a C-H functionalization approach to N-alkylindoles proceeding via a double, site-selective C(sp3)-H/C(sp2)-H [4 + 1] annulation of readily accessed N,N-dialkylanilines. This protocol features a site-selective hydrogen atom transfer by a tuned N-tBu amidyl radical and addition of a sulfonyl diazo coupling partner, which promotes highly site-selective homolytic aromatic substitution of the (hetero)aromatic core. Mild decarboxylation of the annulation product enables the overall introduction of a carbyne equivalent into the N,N-dialkylaniline scaffold. Furthermore, the site-selectivity and mild conditions of the indolization facilitate direct access to N-alkyl indole scaffolds in late-stage functionalization (LSF) settings.

Cobalt and iron metallates as catalysts for cyclization reactions of diynes and triynes: [2+2+2] Cycloaddition vs. Garratt-Braverman reaction

Highly reduced anthracene and naphthalene cobaltates and ferrates catalyze the cyclization of diynes and triynes, furnishing expected [2 + 2 + 2] cycloaddition products as well as unexpected annulation products from Garratt-Braverman cyclization reactions. The anionic Cp*Fe-naphthalene complex exclusively catalyzes the latter reaction. The Garratt-Braverman reactions show a large solvent-dependent substrate conversion. Diynes and triynes afforded the corresponding substituted 1,3-dihydronaphthofurane products with yields up to 91% isolated yield.

Catalyst-Controlled Regiodivergent Oxidative Annulation of 2-Arylimidazo[1,2-a]pyridines with Cinnamaldehyde Derivatives for Construction of Fused N-Heterocyclic Frameworks.

Catalyst-dependent regioselective oxidative annulation of 2-arylimidazo[1,2-a]pyridines with cinnamaldehyde derivatives to construct fused N-heterocyclic frameworks has been described. The annulation reaction afforded 5-arylnaphtho[1',2':4,5]imidazo[1,2-a]pyridine-6-carbaldehydes in the presence of [RhCp*Cl2]2 as catalyst while 1,7-diarylimidazo[5,1,2-cd]indolizine-6-carbaldehydes were obtained using Pd(OAc)2 as catalyst. The reaction produced annulated products in good yields and exhibited broad substrate scope and excellent functional group tolerance. The method provides two different isomeric annulated products bearing an aldehyde functionality which can be elaborated into an array of functionalities leading to valuable compounds.

Theoretical Investigations of Palladium-Catalyzed [3+2] Annulation via Benzylic and meta C-H Bond Activation.

The palladium-catalyzed reaction of aromatic amides with maleimides results in the formation of a double C-H bond activation product, which occurs at both the benzylic and meta positions. Computational chemistry studies suggest that the first C-H bond activation unfolds via a six-membered palladacycle, maleimide insertion, protonation of the Pd-N bond, and then activation of the meta C-H bond. The process concludes with reductive elimination, producing an annulation product. The energy decomposition analysis (EDA) showed that the deformation energy favors the ortho C-H bond activation process. However, this route is non-productive. The interaction energy controls the site where the maleimide is inserted into the Pd-C(sp3 ) bond, which determines its site selectivity. The energetic span model indicates that the meta C-H bond activation step is the one that determines the turnover frequency. Regarding the directing group, it has been concluded that the strong Pd-S bonding and the destabilizing effect of the deformation energy allow the 2-thiomethylphenyl to function effectively as a directing group.

Pd(II)/Lewis Acid Catalyzed Intramolecular Oxidative C−H Amination to Construct Carbazoles with Dioxygen

AbstractTransition‐metal‐catalyzed oxidative C−H amination reactions are among the most attractive topics in organic synthesis to construct nitrogen‐containing motifs. The challenge is that most of these reactions employed stoichiometric oxidants to achieve satisfied catalytic efficiencies. Herein, we report a Pd(II)/LA‐catalyzed (LA: Lewis acid) oxidative C−H amination reaction of 2‐acetaminobiphenyls to construct carbazoles by using dioxygen balloon as the sole oxidant source, and the presence of LA sharply improved the catalytic efficiency of Pd(OAc)2. Remarkably, in certain cases, the deacetylation of the annulation product happened under standard conditions to afford free carbazoles as the final product. The H/D exchange studies confirmed the reversibility of C−H activation and also disclosed multiple C−H activation sites by using −NAc and −NTs as the directing groups. In addition, the palladacycle compound was identified through 1H NMR characterizations and proved to be the intermediate prior to the carbazole formation.

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.

Construction of Thienopyrroles through Rhodium-Catalyzed Direct Annulation of (Acetylamino)thiophenes with Alkynes

AbstractThe direct annulative coupling of 3-(acetylamino)thiophenes with internal alkynes proceeds smoothly under rhodium catalysis through acetylamino-directed C–H bond cleavage at the C2-position, leading to the effective construction of 4-acetylthieno[3,2-b]pyrrole derivatives. The acetyl directing group on the annulation product is readily removed to produce the 4-unprotected thieno[3,2-b]pyrrole derivative.

Mechanistic Exploration of Umpolung Guided Stetter‐Aldol Reaction and Its Dependence on the Choice of Imine

AbstractNHC‐catalyzed Stetter‐aldol reaction for the synthesis of hydroxyindanone takes place via umpolung reactions of phthalaldehyde followed by intramolecular aldol reaction when N‐tert‐butoxycarbonyl (Boc) imine is used and this leads to the formation of [4+1] annulation product. However, this mechanism doesn't follow similar sequence in case of N‐tosyl‐α,β‐unsaturated ketimine and [4+2]‐annulation product is found as the sole product for the latter case through formation of aza‐“Berslow intermediate”. In this study we have used state of the art computational techniques to find out the possible reason for the difference in product and the detailed mechanistic pathway for the above two reactions. Thus, we explain the mechanism for obtaining the selective annulation product ([4+1] vs [4+2]) that can help chemists to design and synthesize a new series of compounds.

Asymmetric Friedel-Crafts reaction of unsaturated carbonyl-tethered heteroarenes via vinylogous activation of Pd0-π-Lewis base catalysis.

The alkyne group can undergo facile transformations under palladium catalysis, such as hydropalladation, Wacker reaction, etc. Here we demonstrate that a chiral Pd0 complex can chemoselectively dihapto-coordinate to the alkyne moiety of 2-indolyl propiolates, and raise the Highest Occupied Molecular Orbital (HOMO)-energy ofthe deactivated heteroarenes via π-Lewis base catalysis. As a result, asymmetric C3-selective Friedel-Crafts addition to activated alkenes occurs, finally affording [3 + 2] or [3 + 4] annulation products with high enantioselectivity and exclusive E-selectivity. Moreover, this π-Lewis base vinylogous HOMO-activation strategy can be extended to remote Friedel-Crafts reaction of diverse five-membered heteroarenes tethered to a 2-enone or 2-acrylate motif with imines or 1-azadienes, and excellent enantiocontrol is generally achieved for the multifunctional adducts, which can be effectively converted to diverse frameworks with higher molecular complexity. In addition, NMR and density functional theory calculation studies are conducted to elucidate the catalytic mechanism.

Sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with Huisgen zwitterions and synthesis of 5-(3-oxindolyl)oxazoles.

Herein, we report a facile synthesis of 5-(3-oxindolyl)oxazole derivatives via a sequential annulation and isomerisation reaction of 3-acylmethylidene oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction exhibits good functional group tolerance with 30 examples of structurally diverse products prepared with moderate to good efficiencies (up to 88% yield), thus providing a generally applicable route to the biologically important 5-(3-indolyl)oxazole structural motifs. Key to the success of this sequential one-pot strategy is the utilization of DBU as a base to promote the isomerisation process of the corresponding intermediate annulation products.

Rh(III)-catalyzed regioselective versatile indole derivatization: delivering potential of rare β-(1H-indol-2-yl)-β-amino acids in one pot.

Rh-catalyzed selective C-H functionalization of indoles with two routes was developed: an alkenylation-annulation with the addition of KHSO4 and alkenylation-elimination in the presence of CsOAc to the corresponding products, respectively. Notably, one-pot hydrolysis and benzoylation of the annulation products successfully afforded easily separable β-(1H-indol-2-yl)-β-amino acid derivatives.