Ring Annulation Research Articles

I2-Catalyzed Aerobic Oxidative C(sp(3))-H Amination/C-N Cleavage of Tertiary Amine: Synthesis of Quinazolines and Quinazolinones.

An iodine-catalyzed oxidative C(sp(3))-H amination/C-N cleavage of tertiary amines couducted under an oxygen atmosphere has been developed and affords a route to quinazolines and quinazolinones in good to excellent yields via a domino ring annulation. The method is metal-free, peroxide-free, and operationally simple to implement with a wide scope of substrates and represents a new avenue for multiple C-N bond formations.

ChemInform Abstract: Fused Imidazopyrazoles: Synthetic Strategies and Medicinal Applications

AbstractReview: 63 refs.

Total synthesis of glycomaurrol and eustifoline-C by DIBAL-H promoted reductive ring opening of pyrano[2,3-c]carbazoles

The palladium-catalyzed construction of the carbazole framework provides an efficient access to 3-hydroxy-6-methylcarbazole (glycozolinine) (5). Regioselective annulation of a pyran ring at glycozolinine (5) using either a C5- or a C10-building block leads to the pyrano[2,3-c]carbazole alkaloids glycomaurin (5,6-pyranoglycozoline, eustifoline-A) (2) and eustifoline-B (4), respectively. Reductive opening of the pyran ring with DIBAL-H in the presence of an additional Lewis acid transformed 2 into the 5-prenyl-substituted carbazole alkaloid glycomaurrol (1) and 4 into the 5-geranyl-substituted homologue eustifoline-C (3).

New Insights into the Hexaphenylethane Riddle: Formation of an α,o‐Dimer

AbstractUpon reduction of a 1H‐cyclobuta[de]naphthalene‐4,5‐diylbis(diarylmethylium) species, a new CC bond is formed between the Cα and Cortho atoms of the two chromophores, which presents an unprecedented coupling pattern for the dimerization of two trityl units. By attaching an annulated cyclobutane ring at the opposite peri position of the naphthalene core, the distance between the Cα carbon atoms was elongated beyond the limit of σ‐bond formation through “scissor effects”. The suppression of CαCα bond formation, which would lead to hexaphenylethane‐type compounds, is key to the first successful isolation of the α,o‐adducts. The 5‐diarylmethylene‐6‐triarylmethyl‐1,3‐cyclohexadiene unit in the α,o‐adducts is stable, and isomerization of the cyclohexadiene unit into an aromatic system was not observed. The newly formed CαCortho bond was cleaved upon two‐electron oxidation to regenerate the dicationic dye.

New insights into the hexaphenylethane riddle: formation of an α,o-dimer.

Upon reduction of a 1H-cyclobuta[de]naphthalene-4,5-diylbis(diarylmethylium) species, a new CC bond is formed between the Cα and Cortho atoms of the two chromophores, which presents an unprecedented coupling pattern for the dimerization of two trityl units. By attaching an annulated cyclobutane ring at the opposite peri position of the naphthalene core, the distance between the Cα carbon atoms was elongated beyond the limit of σ-bond formation through "scissor effects". The suppression of Cα Cα bond formation, which would lead to hexaphenylethane-type compounds, is key to the first successful isolation of the α,o-adducts. The 5-diarylmethylene-6-triarylmethyl-1,3-cyclohexadiene unit in the α,o-adducts is stable, and isomerization of the cyclohexadiene unit into an aromatic system was not observed. The newly formed Cα Cortho bond was cleaved upon two-electron oxidation to regenerate the dicationic dye.

Aromaticity evaluations of planar [6]radialenes.

The aromatic character of fused polycyclic systems varies with the nature of their annulated rings. Computed extra cyclic resonance energies (ECREs) reveal that the central six membered rings (6MRs) of the heterocyclic fused congeners 1-5 are "[6]radialene-like", but that the central 6MRs of triphenylene 9, coronene 10, and isocoronene 11 are "benzene-like." Comparisons with geometric (harmonic oscillator model of aromaticity, HOMA) and magnetic (nucleus independent chemical shifts, NICS) criteria illustrate the multifaceted nature of aromaticity in 1-11.

Asymmetric synthesis of a functionalized tricyclo[6.2.0.02,6]decane ring system present in kelsoene and poduran

Synthesis of a functionalized tricyclo[6.2.0.02,6]decane derivative in enantiomerically pure form, the core structure present in the natural products kelsoene and poduran, is described. The key steps involve a stereocontrolled copper (I)-catalyzed intramolecular [2 + 2] photocycloaddition of a 1, 6-diene prepared from D-mannitol to form a substituted bicyclo[3.2.0]heptane derivative and a ring closing olefin metathesis involving the vicinal substituents on the five-membered ring of the bicyclo[3.2.0]heptane derivative. An asymmetric synthesis of a functionalized tricyclo[6.2.0.02,6]decane derivative has been described. The key step involves an intramolecular Cu (I)-catalyzed [2 + 2] photocycloaddition of a 1,6-diene derived from D-mannitol to provide a bicyclo[3.2.0]heptane derivative. Annulation of a five-membered ring on to the five-membered ring of this derivative using RCM provided the title compound.

Combining silver catalysis and organocatalysis: a sequential Michael addition/hydroalkoxylation one-pot approach to annulated coumarins.

A highly stereoselective one-pot procedure for the synthesis of five-membered annulated hydroxycoumarins has been developed. By merging primary amine catalysis with silver catalysis, a series of functionalized coumarin derivatives were obtained in good yields (up to 91%) and good to excellent enantioselectivities (up to 99% ee) via a Michael addition/hydroalkoxylation reaction. Depending on the substituents on the enynone, the synthesis of annulated six-membered rings is also feasible.

A short access to the skeleton of Elisabethin A and formal syntheses of Elisapterosin B and Colombiasin A.

A short stereoselective synthesis of the Elisabethin A skeleton 4 is described, which opens a formal access to the diterpenes Elisapterosin B and Colombiasin A as well. Key reactions were an intermolecular endo-selective Diels-Alder reaction to generate the decalin part of the molecule, a chemo- and diastereoselective allylation of an aldehyde with allylzinc, a palladium ene annulation of the cyclopentane ring, and a novel sulfonium ylide induced fragmentation of a polycyclic ketone. Additional insights have been gained for the crucial epimerization at C-2.

ChemInform Abstract: Gold‐Catalyzed Cyclization of Diynes: Controlling the Mode of 5‐endo versus 6‐endo Cyclization — An Experimental and Theoretical Study by Utilizing Diethynylthiophenes.

AbstractA dual‐gold catalyzed cyclization of 3,4‐diethynylthiophenes generating new heteroaromatic compounds bearing five‐membered annulated ring systems is reported.

Diazepinoporphyrazines containing peripheral styryl substituents and their promising nanomolar photodynamic activity against oral cancer cells in liposomal formulations.

The photochemical properties and photodynamic activity of three porphyrazines (Pzs) containing annulated diazepine rings, including novel demetalated porphyrazine-possessing bis(styryl)diazepine moieties were investigated. The porphyrazines were evaluated in terms of their electronic absorption and emission properties, their tendency to undergo aggregation and photodegradation, as well as their singlet oxygen generation efficiency. The in vitro photodynamic activity of the porphyrazines and their liposomal formulations were examined by using two oral squamous cell carcinoma cell lines. Magnesium(II) tribenzodiazepinoporphyrazine (1) revealed the highest phototoxic effect in both cell lines used, H413 and HSC-3. Encapsulation of Pz 1 into L-α-phosphatidyl-D,L-glycerol:1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes resulted in a nearly threefold increase in photocytotoxicity relative to that of the solution of Pz 1 (IC50 values of 45 and 129 nM, respectively).

Cyanoazulene-based Multistage Redox Systems Prepared from Vinylcyclopropanecarbonitrile and Cyclopentenone via Divinylcyclopropane-rearrangement Approach

A series of 4-cyanoazulene derivatives 1–5 were synthesized from 4-cyanohexahydroazulen-1-one, which was efficiently obtained by the annulation of the seven-membered ring on the cyclopentenone skeleton via the divinylcyclopropane rearrangement. This synthetic protocol is also effective in preparing 1,1′-bi(4-cyanoazulene) (6) and its p-phenylene-extended derivative 7, which undergo multistage redox reactions exhibiting electrochemical amphotericity.

Regioselective Functionalization of Core‐Persubstituted Perylene Diimides

Regioselective functionalization of core per-substituted perylene diimides has been achieved efficiently based on a new versatile building block, named tetrabromotetrachloro-perylene-3,4:9,10-tetracarboxylic acid dianhydride (Br4Cl4-PTCDA), which affords a series of novel chromophores with impressive optoelectronic properties. Direct palladium-catalyzed fourfold intramolecular ring fusion affords successfully unique propeller-shaped biscarbazole[2,3-b]carbazole diimides with six annulated rings.

ChemInform Abstract: 7,9,12b‐Triazabenzo[a]aceanthrylen‐8‐one, the First Representative of a Novel Pentacyclic Ring System and Its Biological Activities.

AbstractThe novel canthin‐4‐one derivative (VI) bearing an annulated pyridine ring is synthetically accessible by a four‐step approach and shows selective cytotoxic activity against Gram‐positive bacteria.

Gold‐Catalyzed Cyclization of Diynes: Controlling the Mode of 5‐endo versus 6‐endo Cyclization—An Experimental and Theoretical Study by Utilizing Diethynylthiophenes

Herein, a dual-gold catalyzed cyclization of 3,4-diethynylthiophenes generating pentaleno[c]thiophenes through gold-vinylidenes and C-H bond activation is disclosed. Various new heteroaromatic compounds--substrate classes unexplored to date--exhibiting three five-membered annulated ring systems could be synthesized in moderate to high yields. By comparison of the solid-state structures of the corresponding gold-acetylides, it could be demonstrated that the cyclization mode (5-endo versus 6-endo) is controlled by the electronic and not steric nature of the diyne backbone. Depending on different backbones, we calculated thermodynamic stabilities and full potential-energy surfaces giving insight into the crucial dual-activation cyclization step. In the case of the 3,4-thiophene backbone, in which the initial cyclization is rate and selectivity determining, two energetically distinct transition states could be localized explaining the observed 5-endo cyclization mode by classical transition-state theory. In the case of vinyl and 2,3-thiophene backbones, the theoretical analysis of the cyclization mode in the bifurcated cyclization area demonstrated that classical transition-state theory is no longer valid to explain the high experimentally observed selectivity. Herein, for the first time, the influence of the backbone and the aromatic stabilization effect of the 6-endo product in the crucial cyclization step could be visualized and quantified by calculating and comparing the full potential-energy surfaces.

Fused Imidazopyrazoles: Synthetic Strategies and Medicinal Applications

The current review summarizes the known synthetic routes of fused imidazopyrazoles. This review is classified into two main categories based on the type of annulations, for example, annulation of the imidazole ring onto a pyrazole scaffold or annulation of the pyrazole ring onto an imidazole scaffold. Some medicinal applications of imidazopyrazoles are mentioned.

Roger F. C. Brown Memorial Issue

Roger F. C. Brown Memorial Issue

Diindole-Annulated Naphthalene Diimides: Synthesis and Optical and Electronic Properties of Syn- and Anti-Isomers

Here we report a selective method for the core-extension of naphthalene diimide (NDI) with two annulated indole rings leading to carbazolo[2,3-b]carbazole diimides (CbDIs) with exclusive syn-connectivity based on a regioselective nucleophilic substitution reaction of Br4-NDI with arylamines, followed by palladium-catalyzed intramolecular C-C coupling. The oxygen analogues of anti-CbDIs, namely anti-benzofurobenzofuran diimides (anti-BfDIs), were obtained from 2,6-Br2-NDI and 2-bromophenol. The syn- and anti-isomers of CbDIs were unambiguously characterized by single-crystal X-ray analysis. The optical properties of the present core-enlarged NDIs were studied, revealing clear differences in the absorption characteristics of the syn- and anti-isomers of CbDI, on one hand, and CbDI vs BfDI derivatives, on the other hand. Cyclic voltammetry studies showed that the redox properties are dependent on the substituents at the CbDI-core and oxygen atom containing BfDIs are more prone to reduction than the respective nitrogen analogues CbDIs. Vacuum-processed organic field effect transistors reveal CbDI and BfDI derivatives with n-channel, p-channel, as well as ambient transport characteristics with mobility values up to 0.2 cm(2)/(V s).

A simple, green, one-pot synthesis of magnetic-nanoparticle-supported proline without any source of supplemental linkers and application as a highly efficient base catalyst

Fe3O4–proline MNPs were synthesized without any supplemental linkers, using an eco-friendly and effective procedure. It is readily loaded onto magnetic nanoparticles in a single step and is capable of promoting a range of synthetically useful reactions at ambient conditions. Functionalized chromene derivatives are synthesized via condensation and ring annulations of 2-hydroxynaphthalene-1,4-dione or 4-hydroxycoumarin, aryl aldehyde and malononitrile in the presence of a catalytic amount of Fe3O4–proline MNPs at room temperature in excellent yields.

The Fit For Purpose Development of S1P1 Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate

A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P1 receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.