Annulation Process Research Articles

A Versatile Pd-Catalyzed Alkyne Annulation Process for Benzo[a]carbazoles and their Anticancer Analogues.

A Pd-catalyzed, simple, and divergent approach for the direct synthesis of benzo[a]carbazoles from internal alkynes and N-tosyl-iodoindoles has been demonstrated. This methodology highlights the influences of reaction media and temperature for the synthesis of either N-protected or N-deprotected benzo[a]carbazoles. This cascade strategy provides a series of electronically different benzo[a]carbazoles with good yields. The synthesized benzo[a]carbazoles were evaluated for in vitro anticancer activity against human lung cancer A549 cells and human breast cancer MDA-MB-231 cells. Notably, two of the representative analogues displayed potent anticancer activity against both cancer cell lines.

Divergent and Synergistic Photocatalysis: Hydro- and Oxoalkylation of Vinyl Arenes for the Stereoselective Synthesis of Cyclopentanols via a Formal [4+1]-Annulation of 1,3-Dicarbonyls.

The controllable divergent reactivity of 1,3-dicarbonyls is described, which enables the efficient hydro- and oxoalkylation of vinyl arenes. Both reaction pathways are initiated through the formation of polarity-reversed C-centered-radical intermediates at the active methylene center of 1,3-dicarbonyls via direct photocatalytic C-H bond transformations. The oxoalkylation of alkenes is achieved under aerobic conditions via a Cu(II)-photomediated rebound mechanism, while the corresponding hydroalkylation becomes possible under a nitrogen atmosphere by the combination of 4CzIPN and a Brønsted base. The breadth of these divergent protocols is demonstrated in the late-stage modification of drugs and natural products and by the transformation of the products to a variety of heterocycles such as pyridines, pyrroles, or furans. Moreover, the two catalytic modes can be combined synergistically for the stereoselective construction of cyclopentanol derivatives in a formal [4+1]-annulation process.

Synthesis of Tetrahydro-2H-thiopyran 1,1-Dioxides via [1+1+1+1+1+1] Annulation: An Unconventional Usage of a Tethered C-S Synthon.

An unprecedented [1+1+1+1+1+1] annulation process has been developed for the construction of tetrahydro-2H-thiopyran 1,1-dioxides. Notably, rongalite acted as a tethered C-S synthon in this reaction and can be chemoselectively used as triple C1 units and as a source of sulfone. Mechanistic investigation indicated that two different carbon-increasing models are involved in this reaction in which rongalite serves as C1 units.

Highly Diastereoselective Synthesis of γ-Lactams Enabled by Photoinduced Deaminative [3 + 2] Annulation Reaction

The photoinitiated deaminative [3 + 2] annulation reaction of N-aminopyridinium salts with alkenes for the synthesis of functionalized γ-lactams is described. This transformation shows good functional group tolerance as well as excellent diastereoselectivity. Preliminary studies suggest that the employed N-aminopyridinium salts generate the key amidyl radical intermediates through N-N bond cleavage via a photoinduced single-electron transfer (SET) process. The amidyl radical species would add to the double bond of alkenes, followed by a radical-mediated annulation process, to afford the desired γ-lactams.

Generation of a poly-functionalized indolizine scaffold and its anticancer activity in pancreatic cancer cells

A highly efficient domino [4 + 2] annulation process was employed to construct a novel indolizine chemical scaffold. Biological investigation led us to identify 6w as a potent anticancer agent. 6w significantly inhibited cell viability in BxPC3 pancreatic cancer, MCF7 breast cancer, and PC3 prostate cancer cell lines with IC50 values of 0.47 ± 0.04, 1.82 ± 0.08 and 2.68 ± 0.08 µM, respectively. Remarkably, 6w showed a weak effect on cell viability of nontumorigenic human keratinocyte cell line HaCaT compared to the above three types of cancer cells. 6w most potently inhibited cell viability of BxPC3 cells, and 6w also potently reduced cell migration and induced apoptosis in BxPC3 cells through activation of caspase-3 and cleavage of PARP in a dose-dependent manner. These results suggest that 6w can be used for the development of potential anticancer drugs for the treatment of pancreatic cancer.

Tropane and related alkaloid skeletons via a radical [3+3]-annulation process

Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. These bicyclic aniline derivatives are hardly accessible via the classical Robinson tropane synthesis and represent a particularly attractive scaffold for medicinal chemistry. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.

Palladium-Catalyzed Asymmetric [3 + 2] Annulation of Vinylethylene Carbonates with Alkenes Installed on Cyclic N-Sulfonyl Imines: Highly Enantio- and Diastereoselective Construction of Chiral Tetrahydrofuran Scaffolds Bearing Three Vicinal and Quaternary Stereocenters.

A multisubstituted tetrahydrofuran building block bearing three vicinal chiral carbon centers widely exists in a broad spectrum of bioactive natural products, and the development of efficient and convenient methods to establish this skeleton remains a challenging task. Herein, we have developed an efficient method for the construction of significant tetrahydrofuran scaffolds bearing three vicinal and α-quaternary chiral carbon stereocenters through Pd-catalyzed asymmetric [3 + 2] annulation of vinylethylene carbonates with alkenes installed on cyclic N-sulfonyl imines. A series of multisubstituted tetrahydrofuran derivatives are obtained in high efficiencies with excellent enantioselectivities and diastereoselectivities. Density functional theory (DFT) studies are accomplished to rationalize the stereocontrol of the annulation process and disclose that methanol could be applied to stabilize the reactive zwitterionic π-allylpalladium via the H-bond interaction.

Eco-friendly synthesis and structural determination of pyrene fused pyrroloquinolinone hybrid

Synthesis of a structurally complex hitherto unexplored novel class of pyrene fused pyrroloquinolinone was achieved in excellent yield via an environmental friendly solid-state melt reaction condition employing multicomponent cascade protocol which involves 1,3-dipolar cycloaddition and subsequent double annulation process. The 1,3-dipole component was derived in situ from diketone and α-amino acid, whereas the Baylis-Hillman adduct synthesized from pyrene-1-carbaldehyde was utilized as a dipolarophile. Structure of the compound was elucidated by 1H and 13C NMR spectroscopic analysis and further confirmed through single crystal X-ray diffraction and the molecular packing was described by using Hirshfeld surface analysis. The structure-reactivity descriptors of the synthesized compound were examined through DFT calculations. The pyrroloquinoline was evaluated for its antibacterial activity against three multi drug resistant bacterial and two fungal pathogens. The MIC value of the tested microbial pathogens were exhibited with minimum (0.156 mg/mL) and maximum (1.250 mg/mL). The antimicrobial results disclosed that compound 6 is considered as a potent candidate for effective therapeutic applications.

Facile Access to Saccharin‐Fused 1,4‐Dihydropyridines through [3+3] Annulation Reactions

AbstractAn efficient approach to saccharin‐fused 1,4‐DHPs has been established by using a [3+3] annulation process. The chemical event was enabled by a Et3N‐catalyzed tandem Michael/aza‐Pinner reaction of alkyl cyclic N‐sulfonyl ketimines as nucleophiles with α,α‐dicyanoolefins. Under mild conditions, the desired products were readily prepared in good to excellent yields and with broad functional group tolerance (up to 95 % yield, 29 examples). Notably, this practical methodology features the synthesis of pentacyclic spirooxindoles bearing a quaternary spiro‐stereocenter.

Mapping Ambiphile Reactivity Trends in the Anti-(Hetero)annulation of Non-Conjugated Alkenes via PdII /PdIV Catalysis.

In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under PdII /PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3-5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII /amine co-catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII /PdIV mechanism involving Wacker-type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

Mapping Ambiphile Reactivity Trends in the Anti‐(Hetero)annulation of Non‐Conjugated Alkenes via PdII/PdIV Catalysis

AbstractIn this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti‐selective carbo‐ or heteroannulation with non‐conjugated alkenyl amides under PdII/PdIV catalysis. Detailed optimization of the reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other carbo/heterocyclic cores via [n+2] (n=3–5) (hetero)annulation. Expansion of scope to otherwise unreactive ambiphilic haloketones through PdII/amine co‐catalysis is also demonstrated. Compared to other annulation processes, this method proceeds via a distinct PdII/PdIV mechanism involving Wacker‐type directed nucleopalladation. This difference results in unique reactivity and selectivity patterns, as revealed through assessment of reaction scope and competition experiments.

Mechanochemically Induced Dehydrogenation Coupling and [3+2] Cycloaddition of Indolizines with Allenes Using Piezoelectric Materials.

A wide range of indolizines with allenes proceeded smoothly under mechanochemically induced conditions via a [3+2] annulation process, affording various substituted pyrrolo[2,1,5-cd]indolizines in good yields. The reaction efficiency was greatly improved by using piezoelectric material as the charge transfer catalyst. The photophysical properties of the resulting pyrrolo[2,1,5-cd]indolizine were characterized.

Additive- and Solvent-Free Tandem Reaction of P(O)−Oh and Epichlorohydrocarbon for the Controllable O-Alkylation Via the Ring-Opening and Annulation Process

Additive- and Solvent-Free Tandem Reaction of P(O)−Oh and Epichlorohydrocarbon for the Controllable O-Alkylation Via the Ring-Opening and Annulation Process

Construction of pyrazole fused spiroketals by a (3 + 2) annulation reaction

A stereoselective (3 + 2) annulation process between 4-bromo pyrazolones and benzofuran-derived azadienes was developed. A series of novel pyrazole fused spiroketals were synthesized in the presence of triethylamine.

DFT characterisation of a PdII → IIII adduct, and a PdII complex formed after oxidative alkenylation of PdII by [Ph(alkenyl)IIII]+, in Pd-mediated synthesis of benzofurans involving PdIV, annulation and chain-walking.

The synthesis of benzofurans by the reaction of the palladium(II) complex Pd{1-C6H4-2-OCH(CO2Et)-C,C}(bipy) (bipy = 2,2'-bipyridine) with hypervalent iodine(III) reagents [Ph(CHCHR)I]+ has been examined by Density Functional Theory. Results highlight the role of oxidative alkenylation to form PdIV intermediates and the role of initial adduct formation in this process, an annulation process facilitated by PdII, and the role of 'chain-walking' at PdII centres to allow formation of the lowest energy product. Computation (R = Me) allows assignment of an initially formed adduct with a 'PdII → IIII' interaction at -50 °C, and, after oxidative alkenylation of PdII and reductive elimination from a PdIV centre via Ar⋯Alkenyl coupling, formation of a second intermediate with a structure consistent with NMR detection (R = n-hexyl) at -30 °C is obtained. This PdII complex, containing a coordinated alkene group in Pd{1-(RHCγCβ)C6H4-2-OCαH(CO2Et)-η2-CαCβ,C}(bipy), undergoes a 5-exo-trig annulation by forming a Cα-Cβ bond to give a complex with a bicyclic carbon skeleton suitable for subsequent formation of benzofurans. A series of facile rearrangements including chain-walking results in formation of a lowest energy complex of three feasible hydrido(alkene)palladium(II) species, leading to decomposition and release of the observed benzofuran isomer isolated under synthesis conditions. The computational study allows reinterpretation of the NMR data reported previously, in particular the determination of barriers in the reaction pathway allowing assignment of structure for key intermediates.

One-pot catalyst-free synthesis of benzopyrroxazine derivatives by a mutually activated sequential annulation process.

A one-pot catalyst-free reaction of o-hydroxyaryl azomethine ylides, vinyl pyridines and paraformaldehyde for the synthesis of benzopyrroxazines is reported, which offers a straightforward and atom-economical procedure for the preparation of benzopyrroxazine derivatives in moderate to excellent yields under mild conditions. A self-catalyzed [3 + 2] annulation through a mutual activation method and a sequential non-catalyzed [5 + 1] annulation process contribute to this strategy. The corresponding control experiments have been conducted to reveal the mechanism of this reaction.

TINJAUAN YURIDIS TERHADAP PEMBATALAN PERKAWINAN DI PENGADILAN AGAMA BUKITTINGGI

This study aims to comprehend the implementation process, judgment analysis, and legal consequences of marriage annulment (case number 09/Pdt.G/2012/PA.Bkt) in Bukittinggi Religious Court. This was a field research using descriptive method and qualitative approach. Data sources were the interviews with Bukittinggi Religious Court judges, case judgment document, and other supporting documents. The result showed that marriage annulment process in Bukittinggi Religious Court was carried out in several stages in accordance with applicable regulations. The judgments referred to the Marriage Law, Government Regulation No. 9 of 1975 concerning the Implementation of Marriage Law, and the Compilation of Islamic Law. The judgment did not mention the legal consequences for children, property, and third parties because the marriage did not last long. However, those legal consequences certainly need to be discussed, namely the law does not apply retroactively to children and third parties, and inherited property must be returned to its original owner.

Iodine‐Catalyzed Double [4+2] Oxidative Annulations for the Synthesis of Bipyrazines from Ketones and Diamines by a Domino Strategy

AbstractAn iodine‐catalyzed double [4+2] oxidative annulation of ketones and diamines is described. A multi‐pathway coupled domino strategy has been developed for the synthesis of substituted dimeric pyrazines under metal‐free conditions. One C−C and four C−N bonds are formed during this double [4+2] oxidative annulation process from two ketones and two diamines.magnified image

Construction of a Pyrimidine Framework through [3 + 2 + 1] Annulation of Amidines, Ketones, and N,N-Dimethylaminoethanol as One Carbon Donor.

An efficient, facile, and eco-friendly synthesis of pyrimidine derivatives has been developed. It involves a [3 + 2 + 1] three-component annulation of amidines, ketones, and one carbon source. N,N-Dimethylaminoethanol is oxidized through C(sp3)-H activation to provide the carbon donor. One C-C and two C-N bonds are formed during the oxidative annulation process. The reaction shows good tolerance to many important functional groups in air, making this methodology a highly versatile alternative, and significant improvement to the existing methods for structuring a pyrimidine framework, especially 4-aliphatic pyrimidines.

Iodine‐Promoted Synthesis of Dipyrazolo/Diuracil‐Fused Pyridines and o‐Amino Diheteroaryl ketones via Oxidative Domino Annulation of 2/4‐Methylazaarenes

AbstractThe iodine‐promoted oxidative domino annulation and carbonylation process has been developed for the synthesis of biologically important azaarene‐substituted bis‐pyrazolo[3,4‐b:4′,3′‐e]pyridines (BPPs), diuracilpyridines and o‐amino diheteroaryl ketones. The domino procedure proceeded with easily available methyl azaarenes, 5‐aminouracils and substituted 5‐aminopyrazoles. This protocol is a simple and metal‐free approach which exhibits high functional group compatibility and broad substrates scope. Moreover, this transformation can be applied for the preparation of dipyrazolo/diuracil‐fused pyridines on a gram scale.magnified image