Palladium-catalyzed Intramolecular Arylation Research Articles

Regioselective Synthesis of the Tetrahydrocarbazole Core of Akuammiline Alkaloids via Palladium-Catalyzed Intramolecular Arylation Reaction.

Tetrahydrocarbazole is the central core for several biologically active alkaloids, and regioselective synthesis of this core is a challenging task. Herein, we report an efficient strategy for the synthesis of this core involving palladium-catalyzed intramolecular arylation reaction with excellent regioselectivity (>99%) starting from N-phenyl-bromoalkene without having any relocation of double bonds via competitive palladium-catalyzed isomerization reaction. Broad functional group tolerance and exclusive regioselectivity have been observed for meta-substituted halide substrates. Furthermore, this reaction can be scalable on the gram scale.

Palladium-catalyzed intramolecular arylation for the synthesis of tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-ones

Palladium-catalyzed intramolecular arylation for the synthesis of tetrahydro-5H-benzo[6,7]azocino[5,4-b]indol-5-ones

A Simple and Efficient Synthesis of Fused Benzo[b]thiophene Derivatives

AbstractA new approach to the synthesis of fused benzothiophene derivatives was developed based on iodine-promoted photocyclization of 4,5-diaryl-substituted thiophenes obtained in three steps from commercially­ available compounds. Comparative analysis showed that photochemical cyclization is a more efficient method for the preparation of fused benzo[b]thiophene derivatives, compared to oxidative coupling of 4,5-diaryl-substituted thiophenes in the presence of iron(III) chloride and palladium-catalyzed intramolecular arylation. This new approach provides an efficient synthesis of functionally substituted naphtho[2,1-b:3,4-b′]dithiophenes, phenanthro[9,10-b]thiophenes, benzo[1,2-b:3,4-b′:6,5-b′′]trithiophenes, as well as new fused heterocycles containing a pyridine ring and/or a carbazole moiety.

Azaindenocorannulenes: Synthesis, Properties, and Chirality.

Palladium-catalyzed intramolecular arylation provides bowl-shaped azaindenocorannulenes 7-9. Crystals of 8 show bowl-in-bowl columnar stacking. A substituent model rationalizes the first reduction potential of 18 related molecular bowls. The absolute configurations of bowls 7 and 9 are correlated with VCD and ECD spectra. The bowl inversion barrier of 9 (>190 kJ/mol) shows it to be more inert configurationally than chiral biaryl, phosphenes, or [ n]helicenes.

P-Chiral Phosphorus Ligands Based on a 2,3-Dihydrobenzo[ d][1,3]oxaphosphole Motif for Asymmetric Catalysis.

Despite the rapid progress in the field of asymmetric catalysis, the search for new, efficient, and practical asymmetric catalytic transformations to facilitate the green synthesis of chiral natural products and drugs will continue to be a major ongoing effort in organic chemistry. Chiral phosphorus ligands have played a significant role in recent advances in transition-metal-catalyzed asymmetric transformations. However, there remain numerous challenging issues of reactivity and selectivity in catalysis. The development of new and efficient chiral phosphorus ligands with new structural motifs remains highly desirable. P-Chiral phosphorus ligands have been overlooked and are underdeveloped, except for the early success of DIPAMP, introduced first by Knowles in the early 1970s. It was not until the late 1990s that the development of P-chiral phosphorus ligands regained attention with the advent of bisP*, TangPhos, etc. Nonetheless, most P-chiral phosphorus ligands were either difficult to prepare or operationally inconvenient. The development of efficient, practical, and operationally convenient P-chiral phosphorus ligands with new structural motifs remains an important subject of research. This Account introduces the design and development of a series of practical and efficient P-chiral bis- and monophosphorus ligands based on a 2,3-dihydrobenzo[ d][1,3]oxaphosphole motif. Their unique structural and physical properties include conformational unambiguousness, high tunability of electronic and steric properties, and operational simplicity as air-stable solids, which make them practical and exceptional ligands for asymmetric catalysis. Chiral bisphosphorus ligands such as MeO-BIBOP (L3), WingPhos (L4), and iPr-BABIBOP (L7) have demonstrated excellent enantioselectivities and unprecedented turnover numbers (TONs) in various asymmetric hydrogenations and other transformations, providing practical and efficient solutions leading to chiral amines, alcohols, carboxylic acids, and α- and β-amino acids. Chiral biaryl monophosphorus ligands, including BI-DIME (L9), AntPhos (L15), iPr-BI-DIME (L11), etc., have proven to be a class of versatile and powerful ligands for a number of catalytic asymmetric transformations, including asymmetric Suzuki-Miyaura coupling, asymmetric palladium-catalyzed dearomative cyclization, asymmetric hydroboration/diboration, asymmetric nickel-catalyzed reductive coupling, asymmetric palladium-catalyzed intramolecular arylation, asymmetric alkene aryloxyarylation, asymmetric α-arylation, asymmetric Heck reaction, and asymmetric nucleophilic addition, providing efficient solutions leading to various synthetically challenging chiral structures such as chiral biaryls, chiral tertiary alcohols, chiral α-amino tertiary boronic esters, and chiral all-carbon quaternary stereocenters. The high enantioselectivities and TONs obtained with these ligands have resulted in the syntheses of several chiral natural products and therapeutic agents in concise and highly efficient manners. While our efforts on the development of P-chiral phosphorus ligands are ongoing, it should be emphasized that the development of ligands and catalysts with new structural motifs should continue in the search for new reactivity and selectivity to tackle current synthetic challenges. Such effort is destined to promote the advances of asymmetric catalysis as well as synthetic organic chemistry.

Synthesis of Spiro-dihydroquinoline and Octahydrophenanthrene Derivatives via Palladium-Catalyzed Intramolecular Oxidative Arylation

A method for intramolecular sp2 C-H oxidative arylation of unactivated cyclic olefins has been developed to access spiro-dihydroquinoline and octahydrophenanthrene derivatives in a straightforward and efficient manner. Bearing picolinamide as a directing group, the alkenyl anilines cyclized to afford spiro-dihydroquinolines in moderate to excellent yields via direct oxidative arylation, while the alkenyl benzylamines furnished the octahydrophenanthrene derivatives in moderate yields via sequential oxidative arylation and double acetoxylation.

Synthesis of Tricyclic Isoxazoles via Sequential [3+2] Dipolar Cycloaddition­ and Palladium-Catalyzed Intramolecular Arylation Reactions

An efficient synthetic route to tricyclic isoxazoles via sequential copper-catalyzed 1,3-dipolar cycloaddition and palladium-catalyzed intramolecular arylation of isoxazoles is described. Based on these reactions, a convenient one-pot synthesis of the tricyclic isoxazoles from terminal alkyne and hydroximoyl chlorides by using a cascade process was also developed.

Synthesis of [1]benzothieno[3,2-b][1]benzothiophene (BTBT) and its higher homologs through palladium-catalyzed intramolecular decarboxylative arylation

We report herein an effective method for the construction of 4- and 7-ring benzo-fused thieno[3,2-b]thiophenes, involving palladium-catalyzed intramolecular decarboxylative arylation as the key step.

DFT studies on the mechanisms of palladium-catalyzed intramolecular arylation of a silyl C(sp3)–H bond

Detailed mechanisms of the intramolecular C(sp3)–C(sp2) bond formation via C(sp3)–H bond activation of a trimethylsilyl (TMS) substituent catalyzed by palladium(0) complexes have been investigated with the aid of density functional theory (DFT) calculations. The results reveal that the favorable catalytic cycle includes oxidative addition, ligand substitution, concerted metalation deprotonation (CMD) and reductive elimination steps. The CMD was found to be the rate-determining step with an overall free energy barrier of 26.4 kcal mol−1. For the analogous CMe3-substituted substrate, the C(sp3)–H bond activation of the CMe3 substituent was calculated to have a high free energy barrier of 29.9 kcal mol−1. Our calculation results show that during the deprotonation process of the TMS C(sp3)–H bond, the adjacent Si atom stabilizes the charge accumulated on the C(sp3)–H carbon and facilitates the C(sp3)–H bond activation due to the ability of Si to engage in Si–C hypervalent bonding.

Palladium-catalyzed synthesis of benzo[ c]pyrimido[1,6- a]azepine scaffold from Morita–Baylis–Hillman adducts: intramolecular 6-arylation of uracil nucleus

Palladium-catalyzed intramolecular arylation at the C-6 position of uracil moiety was examined. Morita–Baylis–Hillman adducts bearing an uracil moiety at the primary position served an efficient way to a benzo[ c]pyrimido[1,6- a]azepine scaffold.

Pd-Catalyzed Heteroannulation Route to 4-Aminoquinazolines via C-H Amidination

A concise synthesis of 4-aminoquinazolines is presented, which involves palladium-catalyzed intramolecular aryl C-H amidination by isonitrile insertion. Starting from easily available N-arylamidines and isonitriles, the reaction proceeds under mild conditions to afford substituted 4-aminoquinazolines with a broad substrate scope and good functional group tolerance in moderate to excellent yields. Notably, sterically hindered isonitriles such as tert-butyl and 2,6-dimethylphenylisonitriles worked well for this process. An advantage of the methodology is the ready availability of the starting materials from commercial aniline derivatives.

Palladium-Catalyzed Intramolecular C(sp2)–H Amidination by Isonitrile Insertion Provides Direct Access to 4-Aminoquinazolines from N-Arylamidines

An efficient method for the synthesis of 4-amino-2-aryl(alkyl)quinazolines from readily available N-arylamidines and isonitriles via palladium-catalyzed intramolecular aryl C-H amidination by isonitrile insertion has been developed.

ChemInform Abstract: A Modified Synthetic Approach to Optically Pure Benzoxazepines from Amino Acid Precursors Using Intramolecular Buchwald—Hartwig C—O Bond‐Formation Reaction.

Palladium-catalyzed intramolecular aryl etherification reaction using bulky binaphthylphosphane ligand is shown to be a convenient method for the synthesis of seven-membered heterocy- cles. Application of this methodology to a naturally occurring pro- teinogenic L-amino acid has led to the synthesis of optically active benzoxazepine ring systems of versatile biological importance.

A Modified Synthetic Approach to Optically Pure Benzoxazepines from Amino Acid Precursors Using Intramolecular Buchwald-Hartwig C-O Bond-Formation Reaction

Palladium-catalyzed intramolecular aryl etherification reaction using bulky binaphthylphosphane ligand is shown to be a convenient method for the synthesis of seven-membered heterocy- cles. Application of this methodology to a naturally occurring pro- teinogenic L-amino acid has led to the synthesis of optically active benzoxazepine ring systems of versatile biological importance.

ChemInform Abstract: Synthesis of Dibenzazepinones by Palladium‐Catalyzed Intramolecular Arylation of o‐(2′‐Bromophenyl)anilide Enolates.

A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. The reactions were completed in 10 min at 100 °C with moderate to excellent yields. Aminodibenzazepinone 1, the core structure in the γ-secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.

Synthesis of Dibenzazepinones by Palladium-Catalyzed Intramolecular Arylation of o-(2′-Bromophenyl)anilide Enolates

A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. The reactions were completed in 10 min at 100 °C with moderate to excellent yields. Aminodibenzazepinone 1, the core structure in the γ-secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.

Palladium-catalyzed intramolecular decarboxylative allylic arylation of α-aryl-γ-methylidene-δ-valerolactones

A palladium-catalyzed intramolecular decarboxylative cyclization of alpha-aryl-gamma-methylidene-delta-valerolactones, followed by olefin isomerization, has been developed to give fused polycyclic aromatic compounds under mild conditions. The process described here can be regarded as a formal decarboxylative allylic arylation without using a pre-formed organometallic nucleophile. The reaction can be conducted on a gram scale and the products thus obtained are further derivatized with ease.

Palladium-catalyzed intramolecular arylation of pyrimidines: a novel and expedient avenue to benzannulated pyridopyrimidines

A new efficient protocol for the synthesis of benzannulated pyrido[2,3- d]- and pyrido[3,2- d]pyrimidines has been successfully accomplished via the palladium-catalyzed intramolecular arylation of C–H bond of pyrimidine moiety. The methodology has also been extended to the synthesis of pyrimido[5,4,- c]isoquinoline-2,4,6(1 H,3 H,5 H)-trione derivatives in excellent yields.

Convenient Synthesis of 3-Alkoxy-3-aryloxindoles by Intramolecular Arylation of Mandelic Amides

Medicinally important 3-alkoxy-3-aryloxindoles are conveniently prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides.

Bidentate phosphines as ligands in the palladium-catalyzed intramolecular arylation: the intermolecular base-assisted proton abstraction mechanism

The palladium-catalyzed arylation of aryl bromides can be carried out in the presence of bidentate phosphines, such as dppm, dppe, dppf, and Xantphos under mild conditions. The experimental results and the DFT calculations fully support for this reaction a mechanism proceeding by an intermolecular proton abstraction.