Intramolecular Friedel-Crafts Type Research Articles

Enantioselective Synthesis of α-Quaternary Isochromanes by Oxidative Aminocatalysis and Gold Catalysis.

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α-branched aldehydes and propargylic alcohols are transformed into α-quaternary ethers with excellent optical purities (>90 % ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter. A second approach explores the use of allylic alcohols as reaction partners for the oxidative coupling to furnish α-quaternary ethers with generally lower enantiopurities. Stereoretentive cyclization to isochromane products is achieved via intramolecular Friedel-Crafts type alkylation with allylic acetates as a reactive handle. A number of synthetic elaborations and a biological study on these α-quaternary isochromanes highlight the potential applicability of the presented method.

Bsi(OTf)3-mediated tandem annulation of 1-aryl isochroman-3-ones with oxygenated arenes: one-pot synthesis of polyoxygenated homotriptycenes.

Bi(OTf)3 (bismuth triflate)-mediated one-pot tandem annulation of oxygenated 1-aryl isochroman-3-ones with oxygenated arenes provides polyoxygenated homotriptycenes in moderate to good yields in MeNO2 at reflux (101 °C) for 10 h under an air atmosphere and easy-operational conditions via intermolecular and intramolecular Friedel-Crafts type procedures. A plausible mechanism is proposed and discussed. This protocol provides a highly effective ring-closure via three carbon-carbon (C-C) bond formations.

Practical Synthesis of 1-Substituted 5-Aminopyrazolo[4,3-d]pyrimidin-7-ones Using Intramolecular Friedel–Crafts Type Cyclization and Its Application to the Synthesis of Pharmaceutically Active Compounds

Practical Synthesis of 1-Substituted 5-Aminopyrazolo[4,3-d]pyrimidin-7-ones Using Intramolecular Friedel–Crafts Type Cyclization and Its Application to the Synthesis of Pharmaceutically Active Compounds

Computational studies of the mechanism of Pd-Catalyzed Intramolecular Friedel–Crafts allylic alkylation of phenols

We previously reported a synthetic method of spirocyclohexadienones using an Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of para-substituted phenol derivatives. However, the mechanism for the step leading to spirocyclization and driving force behind the remarkably easier formation of the five-membered spirocyclohexadienone as compared with the six-membered spirocyclohexadienone were unclear. Herein, detailed density functional theory (DFT) calculations for the spirocyclization were performed to obtain a plausible reason for the observed behavior. In addition, the mechanistic basis of the characteristic ortho-selectivity in the related Pd-catalyzed intramolecular Friedel–Crafts allylic alkylation of meta-substituted phenol derivatives was elucidated. DFT calculations and experimental studies revealed that the ortho-selective allylation proceeded via an unexpected eleven-membered oxapalladacycle-mediated intramolecular Friedel–Crafts type process.

Asymmetric intramolecular Friedel–Crafts reaction catalyzed by a spiropyrrolidine organocatalyst: Enantioselective construction of indolizine and azepine frameworks

The asymmetric intramolecular Friedel–Crafts type Michael reaction of α,β-unsaturated aldehyde with pyrrole, catalyzed by a spiropyrrolidine (SP)-type organocatalyst, has been accomplished, which allows the construction of a series of azepine and indolizine frameworks with high to excellent enantioselectivities (up to 98% ee). Moreover, the substrate scope could be extended to generate a quaternary center in indolizine frameworks (up to 96% ee).

Synthesis of 3,4-Fused Tricyclic Indoles Using 3-Alkylidene Indolines as Versatile Precursors.

In this personal account, our recent studies of novel synthetic methods of 3,4-fused tricyclic indole derivatives using 3-alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4-fused tricyclic 3-alkylidene indolines were developed based on a palladium-catalyzed intramolecular Heck insertion to an allene-allylic amination cascade and a platinum-catalyzed intramolecular Friedel-Crafts type C-H coupling-allylic amination cascade. Furthermore, three types of 3,4-fused tricyclic indoles were accessible from a single 3-alkylidene indoline precursor via acid-promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4-fused tricyclic indole skeleton, (-)-aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.

Curtin-Hammett-Driven Intramolecular Cyclization of Heteroenyne-Allenes to Phenanthridine-Fused Quinazoliniminiums.

Intramolecular cyclization of the heteroenyne-allene 2-((biphenyl-2-ylimino)methyleneamino)benzonitrile 1 to phenanthridine-fused quinazoliniminium salt PQ in the presence of a Lewis acid at room temperature involves formation of two new bonds: a C-C bond and a C-N bond. In this article, density functional theory (B3LYP and M06-2X) was employed in conjunction with 6-311G* basis set to gain insights into the mechanism of this cyclization reaction. The solvent effects were considered using Polarizable Continuum Model with nitromethane as the solvent. Our calculations show that C-C bond formation precedes the C-N bond formation. Precisely, the mechanism involves initial protonation of 1 at Nα and Nβ of the carbodiimide to form rapidly equilibrating conformers of the tautomers 2a,b and 3a,b. The Curtin-Hammett principle is invoked to determine the course of the reaction from these protonated species, which predicts that the intramolecular Friedel-Crafts type N-acylation (C-C bond formation) occurs between the protonated carbodiimide and biphenyl ring of the isomer 3b to form phenanthridinium cation 6b via transition state TS3b6b. Once 6b is formed, it converts to its most stable tautomers 8R and 9a. Once again, the Curtin-Hammett principle suggests that intramolecular nucleophilic attack is preferred from the tautomer 8R, where phenanthridine N-atom (Nβ) attacks the protonated nitrile group (C-N bond formation) and results in the formation of intermediate 11 via TS8R11. 11 then tautomerizes to the most stable cation 13. The coordination of the latter with the chloride anion yields the phenanthridine-fused heterocyclic salt PQ with overall release of energy. The pathways involving protonation at the nitrile (Nγ) of 1 were found to be energetically unfavorable and thus insignificant to the mechanism of cyclization.

ChemInform Abstract: Enantioselective Organocatalytic Construction of Spiroindane Derivatives by Intramolecular Friedel—Crafts‐Type 1,4‐Addition.

AbstractA highly selective organocatalytic enantioselective intramolecular Friedel—Crafts type cyclization of cycloalkenone onto a resorcin‐type substituent is developed to give a range of spirocyclic indanes.

ChemInform Abstract: 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.

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.

Di- and triheteroarylalkanes via self-condensation and intramolecular Friedel–Crafts type reaction of heteroaryl alcohols

An efficient synthetic approach to diheteroarylmethanes and 1,3-diheteroarylpropenes has been developed via Yb(III)-catalyzed sequential self-condensation of 2-furfuryl (or 2-thienyl or 3-indolyl) alcohols followed by intramolecular Friedel-Crafts type reaction and elimination of an aldehyde. This method offers a powerful entry and a potential alternative to the traditional synthesis of diheteroarylalkanes, which are precursors to the synthesis of several intriguing heteroaryls and more significantly, to the synthesis of biofuels.

Synthesis of the Tetracyclic Core (ABCE Rings) of Daphenylline

A concise synthesis of the tetracyclic core (ABCE rings) of daphenylline has been accomplished involving a benzobicyclo[3.3.1] lactam as the key intermediate. This bridged bicyclic intermediate was efficiently constructed via a Brønsted acid promoted intramolecular Friedel-Crafts type Michael addition of a δ-benzyl α,β-unsaturated δ-lactam.

Synthesis and Optoelectronic Properties of Hexahydroxylated 10‐O‐R‐Substituted Anthracenes via a New Modification of the Friedel–Crafts Reaction Using O‐Protected ortho‐Acetal Diarylmethanols

A new modification of the Friedel-Crafts type intramolecular cyclization involving O-protected ortho-acetal diarylmethanols as a new type of reactant, was carried out for the first time in a medium containing a large amount of water at room temperature and enabled synthesis of a series of electron-rich, hexahydroxylated 10-O-R-substituted anthracenes, where R is an alkyl (Me, nBu, n-C(16)H(33)) or arylalkyl group (CH(2)Ph, CH(2)-2-Napht, CH(2)C(6)H(4)CH(2)OAr) and also evaluation of their electronic and optoelectronic properties in solution, crystal, and solid thin film. In this transformation, a central 10-O-R-substituted benzene ring was formed, fused to rings originating from two independent aromatic aldehydes. The reaction proceeded via two identified mechanisms involving acetal and/or free aldehyde groups. The acid sensitive acetal and dibenzyl alkoxy functions have never been used together in the intramolecular Friedel-Crafts type cyclization. The new compounds revealed deep blue fluorescence and quantum yields in solution around 0.3. The electrical properties investigated for thin films obtained by vacuum deposition on glass were 10-O-R-substituent dependent and showed much faster transient current decay in the case of the 10-O-CH(2)Ph derivative than for the material with a 10-O-Me substituent (the lifetime of charge carriers was 25 times shorter in this case). The AFM images of thin films, Stokes shifts, and X-ray analysis of π-stacking interactions in crystals of the new materials have been also obtained.

ChemInform Abstract: A Practical and Enantioselective Approach to Tetrahydrocarbazoles by Asymmetric Organocatalysis.

AbstractThe intramolecular Friedel—Crafts‐type alkylation of ω‐indolyl α,β‐unsaturated aldehydes in the presence of chiral amines affords the title carbazole derivatives with up to 98% enantioselectivity.

Intramolecular Friedel–Crafts type reaction of vinyloxiranes linked to an ester group

The 7- endo Friedel–Crafts cyclization of arylpropyl vinyloxiranes was found to proceed regio- and stereoselectively to afford polyfunctional seven-membered carbocycles in excellent yields.

A concise synthesis of chilenine via a sequential reaction process

A new short synthesis of chilenine has been achieved in two steps. The precursor amide was readily prepared by the condensation of the corresponding amine and acid. Treatment of the amide with oxalyl chloride in the presence of AlCl 3 at room temperature afforded the desired product chilenine through sequential Friedel–Crafts acylation, amide cyclization to imide, and intramolecular Friedel–Crafts type reaction. The synthesis suggests a new potential of oxalyl chloride for a two-carbon synthon.

Formal synthesis of (−)-morphine from d-glucal based on the cascade Claisen rearrangement

The formal synthesis of (−)-morphine is described. The C-ring in morphine was prepared in an optically pure form from d-glucal using Ferrier’s carbocyclization reaction, and the vicinal tertiary and quaternary stereocenters in the C-ring were stereoselectively generated in a one-step reaction based on the cascade sequential Claisen rearrangement of an allylic vicinal diol derivative. After the one-step formation of the dibenzofuran structure, the intramolecular Friedel–Crafts type reaction effectively constructed the ABCE-phenanthrofuran skeleton. Introduction of a tosylamide function, followed by reductive cyclization furnished (−)-dihydroisocodeine, the known synthetic intermediate for (−)-morphine.

Synthesis of Novel Triphenylene-Type Cations Containing Both Thiophene Rings and a Tropylium Ion Ring. Cyclohepta[e]thieno[2,3-g]benzodithiophenylium Ion and Cyclohepta[e]thieno[3,2-g]benzodithiophenylium Ion

An isomeric pair of cyclohepta[e]thieno[g]benzodithiophenylium ions has been synthesized by an intramolecular Friedel-Crafts type reaction of 2(3)-thienyl-3(2)-cycloheptatrienylthiophenes in a one-pot reaction. These are the isoelectronic cations of triphenylene having both electron-rich and electron-deficient aromatic rings, thiophene and tropylium ion, respectively, in place of phenyl rings.

InCl3‐Catalyzed Tandem Michael/Friedel—Crafts Cyclization: A Novel Protocol for Chiral 2,4‐Disubstituted Tetrahydroquinolines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Bismuth Triflate Catalyzed Condensation of δ‐Hydroxy‐α,β‐Unsaturated Aldehydes with Aryl Amines.

AbstractFor Abstract see ChemInform Abstract in Full Text.