Intramolecular Friedel-Crafts Reaction Research Articles

ChemInform Abstract: A Novel Entry to Spirofurooxindoles Involving Tandem Dearomatization of Furan Ring and Intramolecular Friedel—Crafts Reaction.

AbstractThe key step involves an intramolecular Friedel—Crafts reaction of the tethered electron‐rich anilide with the oxocarbenium derived from the furan ring.

Rapid Generation of Molecular Complexity in the Lewis or Brønsted Acid-Mediated Reactions of Methylenecyclopropanes

Although they are highly strained, methylenecyclopropanes (MCPs) are readily accessible molecules that have served as useful building blocks in organic synthesis. MCPs can undergo a variety of ring-opening reactions because the release of cyclopropyl ring strain (40 kcal/mol) can provide a thermodynamic driving force for reactions and the π-character of the bonds within the cyclopropane can afford the kinetic opportunity to initiate the ring-opening. Since the 1970s, the chemistry of MCPs has been widely explored in the presence of transition metal catalysts, but less attention had been paid to the Lewis or Brønsted acid mediated chemistry of MCPs. During the past decade, significant developments have also been made in the Lewis or Brønsted acid mediated reactions of MCPs. This Account describes chemistry developed in our laboratory and by other researchers. Lewis and Brønsted acids can be used as catalysts or reagents in the reactions of MCPs with a variety of substrates, and substituents on the terminal methylene or on the cyclopropyl ring of MCPs significantly affect the reaction pathways. During the past decade, we and other researchers have found interesting transformations based on this chemistry. These new reactions include the ring expansion of MCPs, cycloaddition reactions of MCPs with aldehydes and imines, cycloaddition reactions of MCPs with nitriles in the presence of strong Brønsted acid, radical reactions of MCPs with 1,3-dicarbonyl compounds, intramolecular Friedel-Crafts reactions of MCPs with arenes, acylation reactions of MCPs, and the reaction of MCPs with 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers. These Lewis or Brønsted acid mediated reactions of MCPs can produce a variety of new compounds such as cyclobutanones, indenes, tetrahydrofurans, and tetrahydroquinolines. Finally, we have also carried out computational studies to explain the mechanism of the Brønsted acid mediated reactions of MCPs with acetonitrile.

Synthesis and Structures of a Series of Bulky “Rind-Br” Based on a Rigid Fused-Ring s-Hydrindacene Skeleton

Abstract A series of octa-R-substituted bromo-s-hydrindacenes, “Rind-Br,” have been synthesized by a sequence of the Lewis acid catalyzed intramolecular Friedel–Crafts reaction, bromination and vice versa. Their structural features and physical properties depend on the eight R-substituents at the four benzylic positions on the s-hydrindacenyl skeleton. The molecular structures of the Rind-Br have been confirmed by X-ray crystallography, indicating the unique structural diversities of the bulky Rind groups.

Synthesis of decahydropyrrolo[2,1,5-cd]indolizine derivatives through RuCl3/AgOTf induced alkene–alkene and alkene–arene double cycloisomerizations

In the presence of RuCl3/AgOTf, pyrrolizidine derivative with styrenyl substituents at the 3,5-positions undergo a 6-exo-trig cyclization and subsequent intramolecular Friedel–Crafts reactions to form decahydropyrrolo[2,1,5-cd]indolizine or decahydrocycl[3.2.2]azine derivatives. The cycloisomerization is highly stereoselective. Presence of electron donating groups on the styrenyl substituents inhibits the double cycloisomerization process and results in a trans to cis epimerization instead. No reaction takes place when electron withdrawing groups are present on the styrenyl substituents. Possible mechanisms are proposed for the observed reactions.

Trifluoroacetic Acid-Promoted Synthesis of 3-Hydroxy, 3-Amino and Spirooxindoles from α-Keto-N-Anilides

Ketoanilides containing alkyl side chains were readily cyclized to 3-hydroxy-2-oxindoles or spirooxindoles by a single or double intramolecular Friedel-Crafts reaction in the presence of trifluoroacetic acid (TFA) at room temperature or at 45 °C. α-Iminocarboxamides, generated in situ from ketoamides, cyclized similarly to 3-aminooxindoles under identical conditions.

ChemInform Abstract: Gold(I)‐Catalyzed Rearrangement of Aryl Alkynylaziridines to Spiro[isochroman‐4,2′‐pyrrolines

AbstractThe novel gold‐catalyzed rearrangement of alkynylaziridines to spiro‐isochromanpyrrolines proceeds via an intramolecular Friedel—Crafts reaction followed by a cyclization of an aminoallene intermediate.

ChemInform Abstract: First Construction of 12H‐Thiochromeno[2,3‐b]quinolines and 5H‐Benzo[7,8]thiocino‐[2,3‐b]quinolines via Intramolecular Friedel—Crafts Reaction of Morita—Baylis—Hillman Adducts.

AbstractAcid‐mediated intramolecular Friedel—Crafts reaction of MBH adducts (III) and (VI) is studied.

Intramolecular Cycloalkylation of Pyrrole in Ionic Liquids and Immobilized Ionic Liquids

The formation of C-C bonds-the basic building blocks of molecules is the most significant chemical phenomena in chemistry. Friedel-Crafts alkylation is among the one in the construction of C-C bond. The alkylation of aromatic rings via Friedel-Crafts alkylation is well established. An intramolecular form of the Friedel-Crafts alkylation has become an effective method for the rapid construction of many carboand heterocyclic compounds. However, due to high reactivity the reaction in certain fused ring systems were found to be of less benefit. Also, heterocyclic rings tend to be poor substrates for the Friedel-Crafts reaction. Over a past decade, ionic liquids (ILs, Figure 1) have gained tremendous potential as a solvent over conventional organic solvents in many organic reactions including nucleophilic substitution reactions. Song et al. have recently reported metal triflate catalyzed Friedel-Crafts alkylation of aromatic compounds with alkenes and alkynes in hydrophobic ILs. Also recently, we have demonstrated that ILs enhance pyrrole C–alkylation regioselectively at C2 position via nucleophilic substitution reaction. Further, our group reported the synthesis of chromane derivatives using intramolecular Friedel-Crafts reaction in IL. In addition, immobilizing IL onto solid supports is the growing field of interest due to easier separation of the catalyst from the reaction media and its possible utilization of the catalyst in a continuous system. Further, polymer forms of ILs were found to have exceptional properties such as stability, electrochemical activity, and high ionic conductivity. Our group has designed a polystyrene supported ionic liquid (PSIL, Figure 1) that can be used for nucleophilic substitution reactions. In extension of our program on alkylations of heteroarenes in IL media, herein, we wish to report cycloalkylation of pyrrole in IL and PSIL as two ecofriendly protocols. Table 1 illustrates intramolecular pyrrole C-alkylation of 1-(4-bromobutyl)-1H-pyrrole (1a) under various reaction conditions. Our initial investigation begins with the entry 1 where the cyclization is performed at the temperature of 100 °C in aprotic organic solvent like acetonitrile without any IL. The reaction afforded 23% of 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine 2a after 24 h. Next, we have performed the same reaction in IL, [bmim][SbF6] in the absence of co-solvent. We observed dark-brown coloration within 1 h. The reaction mixture on thin-layer chromatography showed absence of starting material however, the reaction provided uncharac-

A Novel Entry to Spirofurooxindoles Involving Tandem Dearomatization of Furan Ring and Intramolecular Friedel– Crafts Reaction

AbstractA copper sulfate pentahydrate‐catalyzed intramolecular Friedel–Crafts reaction using an oxocarbenium species derived from a furan ring as the alkylating agent was developed for the first time. By using this protocol, spirofurooxindoles 9 with multi‐reactive sites were synthesized simply and concisely. In addition, selective hydrogenation of the endo‐cyclic double bond and full hydrogenation of the endo and exo‐cyclic double bonds of spirofurooxindoles 9 provided spirofurooxindoles 11 and 12, respectively.

Syntheses of Prekinamycin and a Tetracyclic Quinone from Common Synthetic Intermediates

AbstractTowards total synthesis of a series of kinamycin and related antibiotics via common synthetic intermediates, total synthesis of prekinamycin was achieved via Suzuki coupling of naphthaleneboronic acid and bromobenzene derivative, intramolecular FriedelCrafts reaction of 2‐(naphthalen‐2‐yl)benzoic acid, and diazotization in ten steps from 3,5‐dimethylphenol. Synthetic studies towards kinamycin antibiotics was also examined, and the tetracyclic quinone core for kinamycins was synthesized. Palladium‐catalyzed site‐selective hydroxylation of a benzoic acid derivative with the AB‐D ring part was successfully applied to the selective D‐ring functionalizations.

First construction of 12 H-thiochromeno[2,3- b]quinolines and 5 H-benzo[7,8]thiocino-[2,3- b]quinolines via intramolecular Friedel–Crafts reaction of Morita–Baylis–Hillman adducts

An acid-promoted intramolecular Friedel–Crafts reaction of the Morita–Baylis–Hillman adducts 3 derived from 2-arylthioquinolin-3-carbaldehydes 2 was investigated. Interestingly, promoted by sulfuric acid, the substrates with electron-donating groups on the aromatic ring gave six-membered fused-ring 12 H-thiochromeno[2,3- b]quinolines 4 with good yields, while those with electron-withdrawing groups afforded eight-membered fused-ring 5 H-benzo[7,8]thiocino[2,3- b]quinolines 5 in moderate yields. Using triflic acid instead of sulfuric acid, only products 4 could be obtained under the similar condition.

Synthesis of 1-Tetralones by Intramolecular Friedel-Crafts Reaction of 4-Phenylbutyric Acids Using Modified Zeolite H-BEA

以乙二胺四乙酸二钠（EDTA）、柠檬酸、草酸、酒石酸改性制备了H-BEA,并根据XRD和NH3-TPD对沸石H-BEA进行表征。采用上述改性沸石催化4-苯基丁酸分子内付克反应合成1-萘满酮进行催化剂反应活性评价。实验结果表明,以柠檬酸改性沸石H-BEA具有较高的催化活性。进一步对催化剂用量、反应温度、反应时间等工艺条件优化得到最佳工艺条件,在最佳工艺条件下,产物1-萘满酮产率达到94.3%。

Microwave-Assisted, Yb(OTf)3 /TfOH Cocatalyzed Synthesis of Xanthones and Thioxanthones by Intramolecular Friedel-Crafts Reaction under Solvent-Free Conditions

A novel efficient protocol for the preparation of the biologically interesting title compounds (II) and (IV) including an easy and clean work-up is presented.

Synthesis of Seco-Chlorinated Derivatives of Phenanthroindolizidine Precursors via Friedel-Crafts Reaction

In the course of synthesizing 3-demethyltylophorine (1) by Lewis acid catalyzed intramolecular Friedel-Crafts reaction starting from N-(3-hydroxy-2,6,7-trimethoxy-phenanthr-9-ylmethyl)-2-chloromethylpyrrolidine, two chlorinated phenanthrene derivatives N-(4,10-dichloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (4) and N-(4-chloro-3-hydroxy-2,6,7-trimethoxyphenanthr-9-ylmethyl)-2-chloromethylpyrrolidine (5) were obtained. The structures of these compounds were determined by spectroscopic analysis.

Selective sp3 C–H Bond Activation Based on a Carbocation Relay: Friedel–Crafts Reaction with Alkanes as the Alkylating Component

AbstractA highly efficient and selective intramolecular Friedel–Crafts reaction of 3‐methylbutyl or 4‐methylpentyl‐substituted aromatics has been developed using a carbocation relay strategy through selective sp3 C–H bond activation, providing a facile and cost‐effective approach for the construction of benzocyclic compounds. A variety of 1,1‐dimethylindane and naphthalene derivatives have been prepared from very simple starting materials in good yields with high selectivity. The present strategy has provided a new example of a Friedel–Crafts reaction with alkanes as the alkylating component and constitutes a convenient approach to selective C–H bond activation and functionalization of alkane derivatives.

ChemInform Abstract: A New Synthesis of 7,12-Dihydro-12-phenyl-5H-6,12-methanodibenz(c,f) azocines via N-Benzyl-1,2,3,4-tetrahydro-4-phenylisoquinolin-4-ols.

7,12-Dihydro-12-phenyl-5H-6,12-methanodibenz [c,f] azocine derivatives were prepared from N-benzyl-1,2,3,4-tetrahydro-4-phenyl-isoquinolin-4-ols by an intramolecular Friedel-Crafts reaction

ChemInform Abstract: Synthesis of Saulatine.

A study directed toward the synthesis of saulatine (5,8,9,14a-tetrahydro-3,4,11,12-tetramethoxy-isoquino[1,2-b]benzazepine-6,14-dione) is described. The successful synthetic route consists of three steps starting with 3,4-dimethoxyphenethylamine and 2-bromo-(3,4-dimethoxy-2-ethoxycarbomethylphenyl)-acetate. It was found that the methoxy moieties present on the aromatic rings prohibit the use of the intramolecular Friedel-Crafts reaction with a Lewis acid catalyst for ring construction because of their demethylation tendency under the reaction conditions.

Efficient Synthesis of Phenanthridines Using Hendrickson Reagent Initiated Cascade Reaction under Mild Conditions

A number of variously substituted phenanthridines have been synthesized using the newly developed methodology under mild conditions. The Hendrickson reagent initiated cascade annulation, which is composed of a mild conversion of stable amide precursor to highly reactive imido-carbonium intermediate and a subsequent intramolecular Friedel-Crafts reaction, successfully served as the key method.

Total Synthesis and Biological Evaluation of the Resveratrol-Derived Polyphenol Natural Products Hopeanol and Hopeahainol A

The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol (2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C(7b) quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon global deprotection, hopeahainol A (3). The latter was converted under basic conditions to hopeanol (2), whereas the reverse transformation, previously suggested as a step in the biosynthesis of hopeahainol A (3), was not observed under a variety of conditions. Biological evaluation of the synthesized compounds confirmed the reported acetylcholinesterase inhibitory activity of hopeahainol A (3) but not the reported cytotoxic potencies of hopeanol (2).

BF3⋅OEt2‐Catalyzed Intermolecular Reactions of Vinylidenecyclopropanes with Bis(p‐alkoxyphenyl)methanols: A Novel Cationic 1,4‐Aryl‐Migration Process

BF(3)OEt(2)-catalyzed reactions of vinylidenecyclopropanes (VDCPs) 1 with bis(aryl)methanols 2 were thoroughly investigated. When VDCPs 1 reacted with electron-rich bis(aryl)methanols 2, diastereomeric rotamers of indene derivatives formed in excellent yields by a novel cationic 1,4-aryl migration between two carbon atoms and the subsequent intramolecular Friedel-Crafts reaction pathways in the presence of BF(3).OEt(2) under mild conditions. As for electron-deficient or less-electron-rich bis(aryl)methanols 2, either trialkene products formed in good yields by direct deprotonation, or another type of indene derivative was produced by direct intramolecular Friedel-Crafts reaction, depending on the substituents on the cyclopropane of VDCPs. In addition, DFT calculations were carried out to explain the experimental results. Plausible mechanisms for all these transformations are proposed on the basis of the experimental and computational results.