Intramolecular Friedel-Crafts Alkylation Research Articles

Theoretical Investigation on Intramolecular Friedel-Crafts Alkylation Of 2,2′-Disubstituted 1,3-Indandione Delivering Axially Chiral Biaryls Catalyzed by Chiral Phosphoric Acid

Our Density Functional Theory (DFT) calculations provide the first theoretical investigation on CPA-catalyzed intramolecular Friedel-Crafts alkylation of 1,3-indandione. The reaction is initiated by bis-coordination of CPA with carbonyl and phenol of indandione. The promotion of CPA lies in H-bridge and steric effect from big silyl substituents confirming less-hindered Re-face more favorable than more-shielded Si-face within central chiral alcohol. Next AlCl3-promoted process contains four steps. The dehydration gives positive carbocation, the rearrangement of which activates another carbonyl. The water reversely splits into hydrogen and hydroxyl to recover phenol. The naphthol is obtained from opening of five-membered ring. The central-to-axial chirality conversion is secured between methyl/phenol substituents and carboxylic moiety of axially chiral biaryls. The positive solvation effect is suggested by decreased absolute and activation energies in solution compared with in gas. These results are supported by Multiwfn analysis on FMO composition of specific TSs, and MBO value of vital bonding, breaking.

Intramolecular Friedel-Crafts Reaction with Trifluoroacetic Acid: Synthesizing Some New Functionalized 9-Aryl/Alkyl Thioxanthenes.

In this study, a series of halogen-substituted thioxanthenes were synthesized because the most important and biologically active derivatives of xanthenes are thioxanthenes. In order to obtain new thioxanthene derivatives, first, the starting molecules were synthesized by the appropriate reaction methods in two steps. The intramolecular Friedel-Crafts alkylation (FCA) method was used to convert the prepared three aromatic substituted starting alcohol compounds to their corresponding thioxanthenes by cyclization. For the intramolecular FCA reaction of secondary alcohols, which are the starting compounds (1a-1t), organic Bro̷nsted acids, which require more innovative, easier, and suitable reaction conditions, were used instead of halide reagents with corrosive effects as classical FCA catalysts. Trifluoroacetic acid was determined to be the organocatalyst with the best yield. Therefore, some original 9-aryl/alkyl thioxanthene derivatives (2a-2t) were synthesized using the optimized FCA method. In addition, a new sulfone derivative of thioxanthene 3i was prepared by performing the oxidation reaction with one of the obtained new thioxanthene 2i. Thioxanthenes and their derivatives are important heterocyclic structures that contain pharmacologically valuable sulfur and are used in the treatment of psychotic diseases such as Alzheimer's or schizophrenia, as well as a number of potent biological activities.

Total Synthesis of Alanense A through an Intramolecular Friedel-Crafts Alkylation.

The first total synthesis of cadinane sesquiterpenoid alanense A, in which an intramolecular dehydrative Friedel-Crafts alkylation of 2,5-diaryl-2-pentanol is incorporated as a key step, has been achieved. The combinatorial use of p-TsOH·H2O as a catalyst and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a solvent provides 1,1-disubstituted tetrahydronaphthalene in 97% yield. It was also found that the combination of p-TsOH and HFIP is effective for the removal of phenolic MOM ether.

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes.

In this work, we successfully employed electrochemical conditions to promote a Hofer-Moest, intramolecular Friedel-Crafts alkylation sequence. The reaction proceeds under mild conditions, employing carboxylic acids as starting materials. Notably, the electrochemical process performed in batch was adapted to a continuous flow electrolysis apparatus to provide a significant improvement. This catalyst-free, electrochemical approach produces an array of tetrahydronaphthalenes that could be used for API synthesis.

ZnCl2-Promoted Three-Component Reaction of 2-Aminochromenones, Aromatic Aldehydes, and Quinone Monoketals: Access to 5,6-Dihydro-12H-chromeno[2,3-c]isoquinolin-12-one Derivatives.

A three-component reaction of 2-amino-4H-chromen-4-ones, aromatic aldehydes, and 4,4-dialkoxycyclohexa-2,5-dien-1-ones for the concise synthesis of chromeno[2,3-c]dihydroisoquinoline derivatives has been investigated. This reaction involved consecutive ZnCl2-promoted Micheal addition and intramolecular Friedel-Crafts alkylation. This synthetic protocol offered several advantages, including the readily accessible starting materials, good functional group tolerance, and simplicity of operation. Additionally, the structures of products obtained were determined based on X-ray diffraction studies.

Total Synthesis of Salviachinensine A Using a Matteson Homologation Approach

AbstractSalviachinensine A, a natural product obtained from the Chinese medicinal plant Salvia chinensis, was synthesized for the first time by employing Donald Matteson's boronic ester homologation. The use of (R,R)‐dicyclohexylethane‐1,2‐diol (DICHED) enabled the generation of the required stereogenic centers in a highly stereoselective fashion. Salviachinensine A was formed in a one‐pot protecting group cleavage/lactonization/ intramolecular Friedel–Crafts alkylation, followed by Lewis acid‐catalysed cleavage of the acetal protecting groups.

Synthesis of Fluorene Derivatives Via TfOH-catalyzed Intramolecular Friedel-Crafts Alkylation Reactions

Synthesis of Fluorene Derivatives Via TfOH-catalyzed Intramolecular Friedel-Crafts Alkylation Reactions

Synthesis, In Silico and In Vivo Toxicity Assessment of Functionalized Pyridophenanthridinones via Sequential MW-Assisted Intramolecular Friedel-Crafts Alkylation and Direct C–H Arylation

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a-f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a-f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C-H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a-f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study.

Progress toward the De Novo Asymmetric Synthesis of Euphanes.

Progress toward an asymmetric synthesis of euphanes is described. A C14-desmethyl euphane system possessing five differentially substituted and electronically distinct alkenes has been prepared. The route employed is based on sequential metallacycle-mediated annulative cross-coupling, double asymmetric Brønsted acid mediated intramolecular Friedel-Crafts alkylation, and an oxidative rearrangement to establish the requisite C10 quaternary center. These studies have also led to the discovery of a novel euphane-based modulator of the Liver X Receptor.

A concise synthesis of indolin-2-ones via direct acid-catalyzed intramolecular Friedel-Crafts alkylation of 3-chloro-N-(substituted)-2-oxo-N,3-diarylpropanamides

3-Chloro-2-oxo-N,3-diarylpropanamides, readily obtained from aromatic aldehydes and dichloroacetic acid anilides under Darzens condensation conditions or isomerization of 2-chloro-N,3-diaryloxirane-2-carboxamides, proved to be excellent starting compounds for the synthesis 3-chloro(aryl)methyl)-3-hydroxyindolin-2-ones with the formation of a new C(sp2)–C(sp2)- bond via intramolecular Friedel-Crafts alkylation. Under optimized reaction conditions, the title compounds are obtained in a one-pot process, which involves a treatment of N-benzyl-3-chloro-2-oxo-N,3-diarylpropanamides with a CF3CO2H. The reactions proceed with the formation of easily separated by column chromatography anti and syn diastereomeric mixtures with a predominance of 36–49% of the formers.

Synthesis of Indole-Fused Oxepines via C-H Activation Initiated Diastereoselective [5 + 2] Annulation of Indoles with 1,6-Enynes.

A rhodium-catalyzed diastereoselective formal [5 + 2] annulation of indoles with cyclohexadienone-containing 1,6-enynes has been established via indole 2,3-difunctionalization. The reaction, probably proceeding through tandem indole C2-H alkenylation and intramolecular Friedel-Crafts alkylation relay, provides rapid construction of indole-fused oxepines in good to excellent yields with a broad substrate scope. This method also features concomitant construction of cis-hydrobenzo[b] oxepine scaffolds, a core unit found in numerous natural products of important biological activities.

Transition-metal-free intramolecular Friedel-Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives.

In this work, new derivatives (substituted 9-methyl-9-arylxanthenes) of xanthene compounds (5a–l) of possible biological significance were synthesized by developing a new synthesis method. In order to obtain xanthene derivatives, the original alkene compounds to be used as the starting materials were synthesized in four steps using appropriate reactions. A cyclization reaction by intramolecular Friedel–Crafts alkylation was carried out in order to synthesize the desired xanthene derivatives using the alkenes as starting compounds. The intramolecular Friedel–Crafts reaction was catalyzed by trifluoroacetic acid (TFA) and provided some novel substituted 9-methyl-9-arylxanthenes with good yields at room temperature within 6–24 hours. As a result, an alkene compound was used for activation with TFA in the synthesis of xanthene through intramolecular Friedel–Crafts alkylation for the first time.

A Robust Porphyrin‐Stabilized Triplet Carbon Diradical

AbstractThe synthesis of robust high‐spin carbon radicals is an important topic in organic chemistry. Toward this end, several porphyrin‐stabilized radicals have been systematically explored. A singly naphthalene‐fused porphyrin radical was synthesized by a reaction sequence consisting of a Suzuki–Miyaura coupling of β‐borylated porphyrin with 2‐bromobenzaldehyde, addition of mesityl Grignard reagent, intramolecular Friedel–Crafts alkylation, and final oxidation with DDQ or tBuOK/O2. This strategy was also used to synthesize doubly naphthalene‐fused porphyrins and syn‐ and anti‐fused‐anthracene‐bridged porphyrin dimers. While singly naphthalene‐fused porphyrin radical has been shown to be a stable monoradical, doubly naphthalene‐fused porphyrins and anti‐fused‐anthracene‐bridged porphyrin dimers have been shown to be closed‐shell molecules. Finally, the syn‐dimer was characterized as a surprisingly stable radical (t1/2=28 days under ambient air and at 80 °C) that is storable for more than several months, despite its high‐spin triplet ground‐state carbon diradical.

A Robust Porphyrin-Stabilized Triplet Carbon Diradical.

The synthesis of robust high-spin carbon radicals is an important topic in organic chemistry. Toward this end, several porphyrin-stabilized radicals have been systematically explored. A singly naphthalene-fused porphyrin radical was synthesized by a reaction sequence consisting of a Suzuki-Miyaura coupling of β-borylated porphyrin with 2-bromobenzaldehyde, addition of mesityl Grignard reagent, intramolecular Friedel-Crafts alkylation, and final oxidation with DDQ or tBuOK/O2 . This strategy was also used to synthesize doubly naphthalene-fused porphyrins and syn- and anti-fused-anthracene-bridged porphyrin dimers. While singly naphthalene-fused porphyrin radical has been shown to be a stable monoradical, doubly naphthalene-fused porphyrins and anti-fused-anthracene-bridged porphyrin dimers have been shown to be closed-shell molecules. Finally, the syn-dimer was characterized as a surprisingly stable radical (t1/2 =28 days under ambient air and at 80 °C) that is storable for more than several months, despite its high-spin triplet ground-state carbon diradical.

Intramolecular Friedel-Crafts alkylation with a silylium-ion-activated cyclopropyl group: formation of tricyclic ring systems from benzyl-substituted vinylcyclopropanes and hydrosilanes.

A trityl-cation-initiated annulation of benzyl-substituted vinylcyclopropanes (VCPs) with hydrosilanes is reported. Two Si–C(sp3) bonds and one C(sp2)–C(sp3) bond are formed in this process where an intramolecular 6-endo-tet Friedel–Crafts alkylation of a silylium-ion-activated cyclopropane ring is the rate-determining key step. The reaction mechanism is proposed based on computations and is in agreement with experimental observations. The new reaction leads to an unprecedented silicon-containing 6/6/5-fused ring system. A phenethyl-substituted VCP derivative yields another unknown tricycle having 6/6/6 ring fusion by reacting in a related but different way involving a 6-exo-tet ring closure.

Cation Triggered Domino Aza-Piancatelli Rearrangement/Friedel-Crafts Alkylation of Indole-Tethered Furfuyl Alcohols to Access Cycloocta[b]indole Core of Alkaloids.

A domino approach to bridged cycloocta[b]indolone through a cascade of aza-Piancatelli rearrangement/Friedel-Crafts alkylation is developed. This transformation has been realized by reaction of an indole-tethered 2-furylcarbinol and substituted aniline in the presence of a Lewis acid to initiate aza-Piancatelli rearrangement followed by an in situ intramolecular Friedel-Crafts alkylation to access bridged tetracyclic frameworks in one pot.

Stereoselective synthesis of 9-vinyl substituted unsymmetrical xanthenes and thioxanthenes

Activated 2°-allylic alcohols derived from 2-aryloxybenzaldehydes and 2-(arythio)benzaldehydes undergo intramolecular Friedel-Crafts alkylation reaction when heated with catalytic amount of a Lewis acid in 1,2-dichloroethane to provide highly E-selective 9-vinyl substituted unsymmetrical novel xanthenes and thioxanthenes in good yields.

Thermally Stable and Well‐Defined Pentadiene‐Derived Copolymers Prepared by Anionic Alternating Copolymerization and Subsequent Controlled Postmodification

AbstractThermally stable and well‐defined hydrocarbon polymers prepared via anionic alternating copolymerization of 1,3‐pentadiene (P monomer: trans (TP) and cis (CP) mixture) and styrene derivatives (S monomer: styrene (St) and 1,1‐diphenylethylene (DPE)) and subsequent hydrogenation and cationic cyclization modifications are reported. The TP/S/CP terpolymerization reveals that an incorporation of S‐alt‐CP sequence into the alternating chain is more favorable, while the S‐alt‐TP insertion is also possible especially under high temperature owing to their competitive energy barriers and thermodynamic properties. Then the resultant copolymers with equimolar amount of the two monomers and predominant linear units are intramolecularly cyclized with CF3SO3H, or hydrogenated with p‐toluenesulfonyl hydrazide, to afford soluble and thermally stable hydrocarbon polymers with controlled Mns and narrow ĐMs. The Tg of cylized polymer increases dramatically (ΔTg > 100 °C) on cyclization between the adjacent CC bond in the P structure and the aromatic ring of S unit through the intramolecular Friedel–Crafts alkylation. On the other hand, the Tg of hydrogenated product slightly decreases (ΔTg ≈ 10 °C) after 98% hydrogenation due to the increasing flexibility of the saturated main‐chain, while the Td increases about 60 °C due to the loss of CC bonds under oxygen atmosphere.

Transition‐Metal Catalyzed Stereoselective γ‐Arylation and Friedel‐Crafts Alkylation: A Concise Synthesis of Indenes

A highly stereoselective [Pd]‐catalyzed arylation of tert‐alkenols, is presented and applied to the synthesis of indenes using intramolecular Friedel–Crafts alkylation sequence. The initial Heck reaction is performed by using water as the green solvent. A simple acid triggers intramolecular alkylation in short reaction times at room temperature. Notably, indenes have been accomplished using a single column chromatography technique.

Stitching up the Belt[n]arenes

A synthetic strategy reported recently in the Journal of the American Chemical Society by Wang and coworkers, who used laser irradiation in the final key step of the synthesis, has led to the formation of highly strained belt[8]arene derivatives. This breakthrough could open doors to more controlled and precise syntheses of zigzag carbon nanotubes.