Intramolecular Alkylation Reaction Research Articles

Total synthesis of dissectol A, using an enediolate-based Tsuji-Trost reaction.

Dissectol A is a rearranged terpene glycoside isolated from several flowering plants. Starting from glucose, the densely functionalized bicyclic structure has been prepared via site-selective oxidation and an intramolecular allylic alkylation reaction with an enediolate as the nucleophile. Despite earlier reports, dissectol A is not effective at inhibiting DevRS signaling in whole-cell Mycobacterium tuberculosis and does not inhibit growth of the bacterium.

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

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

Construction and Functionalization of Highly Strained N -Doped Zigzag Hydrocarbon Belts

Construction and Functionalization of Highly Strained <i>N</i> -Doped Zigzag Hydrocarbon Belts

Synthetic Studies toward Tubiferal A: Asymmetric Synthesis of a Model ABC-Ring Compound

AbstractSynthetic studies on an ABC-ring model of tubiferal A, a triterpenoid isolated from the fruit bodies of the Tubifera dimorphotheca myxomycete, are described. The stereogenic centers at the angular positions were constructed through the stereoselective addition of a C-ring allylborane followed by an Eschenmoser–Claisen rearrangement reaction prior to the formation of the AB-ring system by a double intramolecular alkylation reaction of a dichloro nitrile intermediate.

Rhodium-Catalyzed Enamine Homologation of Sulfides with Triazoles as Carbene Precursor

We report on Rh(II)-catalyzed enamine homologation reactions of triazoles with cyclopropylmethyl sulfides. This reaction proceeds via Dimroth rearrangement of triazoles followed by rhodium-catalyzed ylide formation. This ylide, however, does not undergo classic rearrangement reactions. Instead, it undergoes a selective, intramolecular alkylation reaction to yield cyclopropylmethyl-substituted enamides. The application of this reaction was evaluated with different triazoles and sulfides, which underline the special reactivity of cyclopropylmethyl sulfides (29 examples, up to 83% yield).

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.

Construction of Hydrocarbon Nanobelts

AbstractLinearly fused hydrocarbon nanobelts are a unique type of double‐stranded macrocycles that would serve as not only the powerful hosts in supramolecular science but also the templates to grow zig‐zag carbon nanotubes with defined diameters. Fully conjugated hydrocarbon nanobelts such as belt[n]arenes would also possess unique physical and chemical properties. Despite the importance, both fully conjugated and (partially) saturated hydrocarbon nanobelts remain largely unexplored because of the lack of cyclization methods. Reported here is the construction of nanometer sized H12‐belt[12]arenes based on the strategy to close up all fjords of resorcin[6]arene by means of six‐fold intramolecular alkylation reactions of resorcin[6]arene derivatives. All resulting H12‐belt[12]arenes produce a very similar nanobelt core structure with six benzene rings and six boat 1,4‐cyclohexadiene rings being alternately linear‐fused to give a nearly equilateral hexagonal cylinder. The average long diagonal is around 1 nm and the height of the cylinder is about 0.3 nm. The acquired H12‐belt[12]arenes would be the potential precursors to various hydrocarbon nanobelts including fully conjugated belt[12]arenes.

Construction of Hydrocarbon Nanobelts.

Linearly fused hydrocarbon nanobelts are a unique type of double-stranded macrocycles that would serve as not only the powerful hosts in supramolecular science but also the templates to grow zig-zag carbon nanotubes with defined diameters. Fully conjugated hydrocarbon nanobelts such as belt[n]arenes would also possess unique physical and chemical properties. Despite the importance, both fully conjugated and (partially) saturated hydrocarbon nanobelts remain largely unexplored because of the lack of cyclization methods. Reported here is the construction of nanometer sized H12 -belt[12]arenes based on the strategy to close up all fjords of resorcin[6]arene by means of six-fold intramolecular alkylation reactions of resorcin[6]arene derivatives. All resulting H12 -belt[12]arenes produce a very similar nanobelt core structure with six benzene rings and six boat 1,4-cyclohexadiene rings being alternately linear-fused to give a nearly equilateral hexagonal cylinder. The average long diagonal is around 1 nm and the height of the cylinder is about 0.3 nm. The acquired H12 -belt[12]arenes would be the potential precursors to various hydrocarbon nanobelts including fully conjugated belt[12]arenes.

Toward the Synthesis of a Highly Strained Hydrocarbon Belt

Hydrocarbon belts including fully conjugated beltarenes and their (partially) saturated analogs have fascinated chemists for decades due to their aesthetic structures, tantalizing properties, and potential applications in supramolecular chemistry and carbon nanoscience and nanotechnology. However, synthesis of hydrocarbon belts still remains a formidable challenge. We report in this communication a general approach to hydrocarbon belts and their derivatives. Closing up all four fjords of resorcin[4]arene derivatives through multiple intramolecular Friedel-Crafts alkylation reactions in an operationally simple one-pot reaction manner enabled efficient construction of octohydrobelt[8]arenes. Synthesis of belt[8]arene from DDQ-oxidized aromatization of octohydrobelt[8]arene under different conditions resulted in aromatization and simultaneous [4 + 2] cycloaddition reactions with DDQ or TCNE to produce selectively tetrahydrobelt[8]arene-DDQ2, tetrahydrobelt[8]arene-TCNE2, and belt[8]arene-DDQ4 adducts. Formation of belt[8]arene, a fully conjugated hydrocarbon belt, was observed from retro-Diels-Alder reaction of a belt[8]arene-DDQ4 adduct with laser irradiation under MALDI conditions. The new and practical synthetic method established would open an avenue to create belt-shaped molecules from easily available starting materials.

Decarboxylative Intramolecular Arene Alkylation Using N-(Acyloxy)phthalimides, an Organic Photocatalyst, and Visible Light.

An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.

α-Selective Glycosylation with β-Glycosyl Sulfonium Ions Prepared via Intramolecular Alkylation.

Stereoselective glycosylation remains the main challenge in the chemical synthesis of oligosaccharides. Herein we report a simple method to convert thioglycosides into β-sulfonium ions via an intramolecular alkylation reaction, leading to highly α-selective glycosylations for a variety of glycosyl acceptors. The influence of the thioglycoside substituent and the protecting group pattern on the glycosyl donor was investigated and showed a clear correlation with the observed stereoselectivity.

Conformational analysis of a TADDOL-based phosphoramidite P,N ligand in a palladium(II) η3-π-allyl complex

The most stable conformations of a TADDOL-based phosphoramidite P,N ligand coordinated to a palladium(II) η3-π-allyl fragment have been investigated using molecular mechanical and quantum mechanical calculations. The conformational analysis initially generated 53 unique structures within 5 kcal/mol and subsequent geometry optimization narrowed the number of low-energy conformers down to 13. The two lowest energy conformers differ mainly in the conformation of the allyl group. The conformer with an endo allyl group has a slightly higher relative energy than the conformer with an exo allyl group. Comparison of the main geometric parameters around the Pd(II) metal center in the two lowest energy conformers with the available X-ray single crystal structures of Pd(II) η3-π-allyl complexes of P,N ligands shows a good agreement in both the bond lengths and angles. The lowest energy structure has a “chair” conformation of the seven-membered phospha-dioxa-cycloheptane ring and “edge-on/face-on/face-on/edge-on” arrangement of the phenyl rings. The next lowest energy conformer with an exo allyl group has a “twist” conformation of the seven-membered ring and alternating “edge-on” and “face-on” arrangement of the phenyl rings as anticipated from the Knowles “edge-on/face-on” concept. The results of this study support published hypotheses regarding the origin of the chiral induction in the enantioselective Pd(0) catalyzed intramolecular allylic alkylation reaction by the repulsive interactions between one of the phenyl groups in the seven-membered ring in the lowest energy conformer of the ligand with the substrate. As such, the results of this research can be used to guide the synthesis of new and improved variants of this important catalyst family.

Application of a catalyst-free Domino Mannich/Friedel-Crafts alkylation reaction for the synthesis of novel tetrahydroquinolines of potential antitumor activity

A useful and efficient method to construct diversely substituted 1,2,3,4-tetrahydroquinolines in good to excellent yields has been developed through a catalyst-free Domino Mannich and intramolecular Friedel-Crafts alkylation reactions of N-arylamines with paraformaldehyde and electron-rich olefins via the formation of N-aryl-N-alkylmethyleneiminium ions as the key intermediates to afford the target products. Nine of the new compounds were evaluated in the US National Cancer Institute (NCI), where compound 5f (R1 = 6-MeO, R2 = p-ClC6H4 and X = pyrrolidin-2-onyl) presented a remarkable activity against 57 cancer cell lines, with the most important GI50 values ranging from 1.46 to 8.28 μM from in vitro assays. Further studies performed over the active compound 5f on HCT116 colon cancer cells indicated that its effect on cell death is exerted through a cell cycle arrest (S phase) in a dose dependent manner, as well as suppression on the cell proliferation process.

It Is Not Just Up to the Substrate: Palladium(0) Cyclizes Nazarov Substrates through Intramolecular Allylic Alkylation

Plausible mechanisms of Pd0-catalyzed cyclization of diketoesters were modeled using density functional theory calculations. Comparison of the reaction mechanisms of uncatalyzed and Pd0-catalyzed cyclizations revealed the vital role of the Pd0 catalyst. Both reactions favor a stepwise mechanism involving a proton transfer followed by carbon–carbon bond formation over either the reverse order or a concerted mechanism. The key step for the Pd0-catalyzed reaction is the formation of a relatively stable intermediate, an η3-allyl PdII complex, in the lowest energy pathway. Our proposed mechanism is consistent with a Pd0-catalyzed intramolecular allylic alkylation reaction, previously referred to as “Nazarov-type” reactions. It is worth noting that, in contrast to many allylic alkylations, the Pd0-catalyzed cyclization does not require any additional reagents or an activated leaving group to form an η3-allyl PdII complex; thus, the α-hydroxycyclopentenone is produced from diketoesters with no waste. Furthermore...

Catalytic Intramolecular Ketone Alkylation with Olefins by Dual Activation.

Two complementary methods for catalytic intramolecular ketone alkylation reactions with unactivated olefins, resulting in Conia-ene-type reactions, are reported. The transformations are enabled by dual activation of both the ketone and the olefin and are atom-economical as stoichiometric oxidants or reductants are not required. Assisted by Kool's aniline catalyst, the reaction conditions can be both pH- and redox-neutral. A broad range of functional groups are thus tolerated. Whereas the rhodium catalysts are effective for the formation of five-membered rings, a ruthenium-based system that affords the six-membered ring products was also developed.

Inter- and Intramolecular Annulation Strategies to a Cyclopentanone Building Block Containing an All-Carbon Quaternary Stereogenic Center

Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter- and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center.

ChemInform Abstract: Gold‐Catalyzed Asymmetric Allylic Substitution of Free Alcohols: An Enantioselective Approach to Chiral Chromans with Quaternary Stereocenters for the Synthesis of Vitamin E and Analogues.

AbstractThis new gold‐catalyzed intramolecular allylic alkylation reaction provides chiral chromans for the synthesis of α‐tocopherol [vitamin E (IVc)], γ‐tocopherol (IVe), and its analogs (VII), as well as trolox (VIII) and (S)‐LLU‐a (IX) via a following metathesis reaction.

Enantioselective synthesis of 4-substituted tetrahydroisoquinolines via palladium-catalyzed intramolecular Friedel-Crafts type allylic alkylation of phenols.

Palladium-catalyzed asymmetric intramolecular Friedel-Crafts type allylic alkylation reaction of phenols was developed under mild conditions. In the presence of Pd2(dba)3 with (1R,2R)-DACH-phenyl Trost ligand (L2) in toluene at 50 °C, the reaction provides various C4 substituted tetrahydroisoquinolines with moderate to excellent yields, regioselectivity and enantioselectivity.

Gold-catalyzed asymmetric allylic substitution of free alcohols: an enantioselective approach to chiral chromans with quaternary stereocenters for the synthesis of vitamin E and analogues.

The enantioselective synthesis of α- and γ-tocopherol (the most biologically active members of vitamin E family) and analogues has been accomplished employing a new enantioselective gold catalyzed intramolecular allylic alkylation reaction followed by an olefin cross-metathesis as key steps. The methodology proved to be applicable to different olefins highlighting its potential for the synthesis of diverse libraries.

New developments in redox chemical delivery systems by means of 1,4-dihydroquinoline-based targetor: Application to galantamine delivery to the brain

The therapeutic efficiency of palliative treatments of AD, mostly based on acetylcholinesterase (AChE) inhibitors, is marred by serious adverse effects due to peripheral activity of these AChE inhibitors. In the literature, a redox-based chemical delivery system (CDS) has been developed to enhance drugs distribution to the brain while reducing peripheral side effects. Herein, we disclose two new synthetic strategies for the preparation of 1,4-dihydroquinoline/quinolinium salt redox-based systems particularly well designed for brain delivery of drugs sensitive to alkylation reactions. These strategies have been applied in the present case to the AChE inhibitor galantamine with the aim of alleviating adverse effects observed with cholinergic AD treatment. The first strategy is based on an intramolecular alkylation reaction as key step, whilst the second strategy relies on a useful coupling between galantamine and quinolinium salt key intermediate. In the course of this work, polymer-supported reagents and a solid-phase synthesis approach revealed to be highly helpful to develop this redox-based galantamine CDS.