Regioselective Arylation Research Articles

Three-Component Regioselective Aryl- and Alkenyl-Aminoalkylation of Alkenes via Cooperative Photoredox/Nickel Catalysis.

Recently, metallaphotoredox-catalyzed alkene dicarbofunctionalization reactions have been extensively investigated. Most cases are related to alkyl-arylation processes by conjugate coupling of alkyl radical precursors and aryl electrophiles across alkenes. By contrast, reported examples of alkylvinylation by coupling of vinyl electrophiles are largely limited. Herein, we represent a three-component aminoalkyl-vinylation of alkenes enabled by photoredox/nickel catalysis. This redox-neutral protocol exhibits broad substrate scope and good chemo-, regio- and E/Z-stereoselectivity. A series of valuable α-vinyl γ-amino acid derivatives are conveniently synthesized by the assembly of readily available starting materials.

Copper-Catalyzed Regioselective Arylation or Alkenylation of Quinoline N-Oxides with Organoboronates.

A copper-catalyzed arylation or alkenylation of quinoline N-oxides with aryl- or alkenylboronates, respectively, has been developed, which provides an efficient route for C2-substituted oxygenated quinolines under mild reaction conditions. The reaction shows a broad substrate scope for both quinoline N-oxides and aryl/alkenylboronates, mild reaction conditions, and high reaction efficiency. The formation of an aryl- or alkenyl-copper species as the key intermediate was suggested to be involved in this reaction.

Photoinduced Site-Selective Aryl C-H Borylation with Electron-Donor-Acceptor Complex Derived from B2Pin2 and Isoquinoline.

Due to boron's metalloid properties, aromatic boron reagents are prevalent synthetic intermediates. The direct borylation of aryl C-H bonds for producing aromatic boron compounds offers an appealing, one-step solution. Despite significant advances in this field, achieving regioselective aryl C-H bond borylation using simple and readily available starting materials still remains a challenge. In this work, we attempted to enhance the reactivity of the electron-donor-acceptor (EDA) complex by selecting different bases to replace the organic base (NEt3) used in our previous research. To our delight, when using NH4HCO3 as the base, we have achieved a mild visible-light-mediated aromatic C-H bond borylation reaction with exceptional regioselectivity (rr > 40:1 to single isomers). Compared with our previous borylation methodologies, this protocol provides a more efficient and broader scope for aryl C-H bond borylation through the use of N-Bromosuccinimide. The protocol's good functional-group tolerance and excellent regioselectivity enable the functionalization of a variety of biologically relevant compounds and novel cascade transformations. Mechanistic experiments and theoretical calculations conducted in this study have indicated that, for certain arenes, the aryl C-H bond borylation might proceed through a new reaction mechanism, which involves the formation of a novel transient EDA complex.

Inside Back Cover

Azepine ring is a prominent structural scaffold in biologically significant molecules. This study demonstrates a Ni(II)‐catalyzed alkyne functionalization/cyclization cascade reaction of alkyne‐tethered malononitriles, involving intermolecular regioselective arylation of the alkynes and desymmetrizing addition onto the nitrile group, to access azepine derivatives. This strategy introduces an all‐carbon quaternary stereocenter and an unprotected imine functionality simultaneously to the azepine scaffold, showing great promise for subsequent transformations. More details are discussed in the article by Liu et al. on page 873—878.image

Mechanochemical C-H Arylation and Alkylation of Indoles Using 3 d Transition Metal and Zero-Valent Magnesium.

Although the 3 d transition-metal catalyzed C-H functionalization have been extensively employed to promote the formation of valuable carbon-carbon bonds, the persistent problems, including the use of sensitive Grignard reagents and the rigorous operations (solvent-drying, inert gas protection, metal pre-activation and RMgX addition rate control), still leave great room for further development of sustainable methodologies. Herein, we report a mechanochemical technology toward in-situ preparation of highly sensitive organomagnesium reagents, and thus building two general 3 d transition-metal catalytic platforms that enables regioselective arylation and alkylation of indoles with a wide variety of halides (including those containing post transformable functionalities and heteroaromatic rings). This mechanochemical strategy also brings unique reactivity and high step-economy in producing functionalized N-free indole products.

Streamlined Stereoselective Entry to (-)-Quinagolide and to 3-Substituted Octahydrobenzo[g]-Quinolines.

A very short stereoselective synthesis of enantiomerically pure (3S, 4aS, 10aR)-quinagolide has been developed. The key steps involved are a copper-catalyzed regioselective arylation of (S)-epichlorohydrin with 1,6-dimethoxynaphthalene and a diastereoselective trans-reduction of a cyclic enamine intermediate. The possibility to use both enantiomers of epichlorohydrin and the diastereodivergency found in the reduction process paves the way for a general preparation also in the nonracemic form of chiral trans-fused 3-substituted octahydrobenzo[g]quinolines that are privileged structures in medicinal chemistry.

Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophiles

AbstractWe demonstrate that regioselective aryl transfer to the nucleophile occurs rapidly under mild conditions via reductive elimination and show that regioselectivity is primarily governed by steric factors imparted by ortho substituents on the recipient ring. Computational modeling and x‐ray crystallography confirm that the recipient aryl ring is positioned in the equatorial coordination site and oriented orthogonally to the axial X−Bi−Ph bond (X=nucleophile) in a trigonal bipyramidal structure. The orientation of the ortho‐substituted aryl ring allows the appropriate orbital to overlap between its ipso carbon and nucleophile, which enhances the rate of aryl transfer to the nucleophile and dictates the regioselective reductive elimination from Bi(V) compounds. This level of stereoelectronic control results in significantly enhanced reaction rate and selectivity and creates an opportunity to rationally design ligand systems for selective aryl transfer reactions.

Ni‐Catalyzed Enantioselective Difunctionalization of Alkynes to Azepine Derivatives Bearing a Quaternary Center and an Unprotected Imine†

Comprehensive SummaryThe azepine ring is a prominent structural scaffold in biologically significant molecules. In this study, we present a Ni(II)‐catalyzed asymmetric difunctionalization of alkynes, involving intermolecular regioselective arylation and intramolecular nitrile addition, enabling the synthesis of enantioenriched azepine derivatives. This reaction simultaneously installs an all‐carbon quaternary stereocenter and introduces an unprotected imine functionality, showing great promise for subsequent transformations. The reaction exhibits good tolerance toward various functional groups, resulting in high yields and enantioselectivities. The synthetic utility of this methodology is further demonstrated through gram‐scale synthesis and product derivatization. This research offers an efficient approach to the synthesis of seven‐membered nitrogen heterocycles.

Substituent-controlled regioselective arylation of carbazoles using dual catalysis.

Regioselective arylation of carbazoles is reported using dual palladium-photoredox catalysis. Controlled monoarylation and diarylation of symmetrical and unsymmetrical carbazoles were achieved under mild reaction conditions with a broad substrate scope and functional group tolerance. Steric and electronic control the regioselectivity of the arylation of unsymmetrical carbazoles. Late-stage functionalization of a caprofen drug derivative and large-scale synthesis of mono- and di-arylated carbazoles were demonstrated to showcase the synthetic versatility of the method. Finally, we also showcased the synthesis of hyellazole analogues (a marine alkaloid) in a short route using our strategy.

Palladium-Catalyzed Regioselective Aryl Phenoxylation of Allenamide

Palladium-Catalyzed Regioselective Aryl Phenoxylation of Allenamide

Sequential regioselective arylation of pyrazolones with diaryliodonium salts.

The introduction of aromatic substituents into organic compounds significantly alters their physical and chemical characteristics. Yet, achieving precise control over the site-selectivity of arylation continues to pose a considerable challenge. We present here a controllable method for the site-selective mono-, di-, and triarylation of pyrazolone with diaryliodonium salts. The method showcases robustness, flexibility, and excellent compatibility with a broad range of functional groups. It enables control over both the site of arylation and the number of aryl additions. Specifically, three of the four substitutable positions in pyrazolone can be selectively arylated, effectively producing four products under controlled conditions. Additionally, the method supports one-pot sequential arylation, leading to an array of products with diverse aromatic substituents. Control experiments revealed the specific conditions of each reaction step.

Palladium-Catalyzed Diversified Synthesis of Monofluorinated Alkenes from Allylic gem-Difluorides through Pd-OH Intermediate.

Significant advancements in synthesis of monofluoroalkenes via palladium-catalyzed reactions involving allylic gem-difluorides and diverse nucleophiles have been achieved. This method allows regioselective arylation, alkylation, allylation, alkenylation, and hydrogenation of allylic gem-difluorides, yielding high Z-selectivity and favorable product yields under mild conditions. Tolerating various functional groups, these transformations utilize a common Pd-OH intermediate. Additionally, employing triple Pd-catalyzed cross-coupling yields diverse trisubstituted alkenes efficiently.

Access to Mono‐, Di‐ and Tri‐(Het)Arylated Pyrazolo[5,1‐b]oxazoles Using Cyclization, C−H Activation and Suzuki–Miyaura Palladium‐Catalyzed Reactions

AbstractA first access to mono‐, di‐ and tri‐(Het)arylated pyrazolo[5,1‐b]oxazoles is reported. The series were generated from a library of 3‐(Het)arylpyrazolo[5,1‐b]oxazole platforms selectively functionalized through regioselective arylation procedures. The regioselective functionalization in C‐2 and C‐7 positions was investigated. Each Palladium‐catalyzed cross‐coupling condition was optimized and a representative library of the scope and limitations of the reactions was studied.

Transition Metal-catalyzed Regioselective Direct C-H Arylations Using Quinone Diazide as Arylating Agent: A Mini Review

Abstract: Quinone diazides are a class of diazo compounds, having a planar six-membered ring system with diazo, carbonyl and al-kene groups in conjugation. Earlier it was used in optical, electronic, polymer materials etc. In the last few years, various rearrangements reactions and insertion reactions were explored by these diazo compounds via the formation of metallo-carbenoids. Recently, it has been used to incorporate phenol moieties to hydrocarbons or arene/heteroarenes systems via transition metal-catalyzed C-H bond activation. The reactions proceed via C-H bond insertion or migratory insertion of metal-carbenes. In many cases, the site-selectivities were obtained by the guidance of various directing groups (remova-ble or non-removable). At the same time, several asymmetric approaches were also studied to incorporate phenol deriv-atives to arenes/heteroarenes furnishing compounds showing axial chirality with high stereoselectivity. In this review, we will mainly focus on directed regioselective arylation with quinone diazides under transition metal catalysis through C-H bond activation.

Palladium-catalyzed regioselective arylation of 7-hydroxyflavone with diaryliodonium salts

A palladium-catalyzed regioselective arylation at the C6 position of 7-hydroxyflavone protocol was disclosed for the first time. The reaction occurs in carbamate directing group directed CH activation manner. The key to this high regioselectivity is the appropriate choice of carbamates as protecting/directing groups and H3PO4 additive in the presence of Pd (TFA)2 catalyst. Additionally, the procedure provided an expedient approach for the preparation of 6-arylflavone derivatives.

Nickel-catalyzed Suzuki cross-coupling reaction of alkyl triaryl phosphonium salts

The Suzuki cross-coupling reaction of triphenyl quaternary phosphonium triflates with boronic acids was reported. The reaction was catalyzed by Ni(COD)2 without additional ligand, using Cs2CO3 as the base in toluene, and various biphenyls were synthesized in medium to excellent yields. This protocol has a wide adaptability to boronic acids, and many functional groups are tolerated. The method is scalable and could be performed on the gram scale. The regioselective arylation of differently substituted phenyl phosphonium triflates was observed at the side of electron-deficient phenyl group.

Aryl C-H bond functionalization with diphenyldiazomethane induced by rare-earth metal alkyl complexes.

The first examples of regioselective aryl ortho-C-H functionalization with diphenyldiazomethane for the construction of Caryl-Nhydrazinato bonds were accomplished via the activation of C-H bonds and the subsequent reaction of diphenyldiazomethane with the RE-Caryl bond. The reactions of rare-earth metal monoalkyl complexes LRE(CH2SiMe3)(THF)2 (L = 2,5-[(2-pyrrolyl)CPh2]2(N-Me-pyrrole)) supported by a neutral N-methylpyrrole anchored dipyrrolyl ligand with 2 equiv. of Ph2CN2 gave irreversibly unprecedented hydrazonato-functionalized imino rare-earth metal complexes LRE(Ph2CNNC6H4-(o-CNHPh) (RE = Y (2a), Lu (2a')) in good yields involving a rather complex process including the interaction of a diazo unit with a RE-Calkyl bond, a β-H elimination, a N-N cleavage, 1,4-hydrogen transfer and the subsequent C-N coupling with another diphenyldiazomethane. More important is that regioselective aryl C-H bond functionalization with diphenyldiazomethane to construct the Caryl-Nhydrazinato bonds can be easily achieved by three-component reactions of rare-earth metal monoalkyl complexes, a wide range of substituted imines (including aldimines, ketimines or analogous 2-phenylpyridine) and diphenyldiazomethane, affording various hydrazonato-functionalized phenyl, thienyl imino or pyridyl rare-earth metal complexes 2b-2j at room temperature. A further study indicated that the substituents on the phenyl ring have a great effect on the reaction pathway and governed the Caryl-Nhydrazinato bond construction. Moreover, the experimental studies show that the formation of the Caryl-Nhydrazinato bonds is thermodynamically facile, which could be realized at room temperature easily.

Synthesis of modified bile acids via palladium-catalyzed C(sp3)-H (hetero)arylation.

A Pd(II)-catalyzed strategy for the diastereo- and regioselective (hetero)arylation of unactivated C(sp3)-H bonds in bile acids is accomplished with aryl and heteroaryl iodides under solvent-free conditions using the 8-aminoquinoline auxiliary as a directing group. This methodology demonstrated excellent functional group tolerance with respect to aryl/heteroaryl iodides on O-protected N-(quinolin-8-yl)cholyl/deoxycholyl amides to afford β-C(sp3)-H (hetero)arylated products in good-to-excellent yields. Moreover, the 8-aminoquinoline (AQ) auxiliary can easily be removed to obtain modified bile acids.

Protecting Group‐Controlled Regioselective Synthesis for Unsymmetrical 3,5‐Disubstituted Pyridones

AbstractProtecting group‐controlled regioselective functionalization of 3,5‐dibromo‐2‐pyridones has been studied for preparation of unsymmetrical 3,5‐disubstituted 2‐pyridones. A bulky di‐tert‐butyl(isobutyl)silyl (BIBS) group was utilized for C5 regioselective arylation in Suzuki‐Miyaura reactions. Meanwhile, the p‐toluenesulfonyl (Ts) group was used to maximize C3 selective halogen‐lithium exchange employing flow chemistry. Most of the reactions proceeded well, with yields of 76 to 95% and excellent regioselectivity. A one‐pot synthesis of unsymmetrical 3,5‐diaryl‐2‐pyridones starting from 3,5‐dibromo‐2‐silyloxypyridine was conducted to demonstrate the practical convenience. Further functionalization onto the remaining bromine group, such as transition metal‐catalyzed C−C and C−N bond‐forming reactions and retro‐Brook rearrangement for C−Si bond formation, was accomplished for synthesis of biologically relevant 3,5‐disubstituted 2‐pyridones. Finally, amrinone and milrinone, commonly used for congestive heart failure, were synthesized in three steps from 3,5‐dibromo‐2‐pyridones in 41% and 56% overall yields, respectively.magnified image

Metal‐Free TFA‐Promoted Regioselective (Hetero)Arylation: Synthesis of (Hetero)Aryl Substituted and Carbazole/Oxepine Fused N‐Heterocycles

AbstractMetal‐free TFA promoted arylation/heteroarylation was achieved under mild conditions via the reaction of chloro‐derivatives of nitrogen heterocycles [e. g., =C−C(Cl)=N−] with electron rich arenes/heteroarenes. It was also observed that apart from participating in the heteroarylation step, TFA was able to facilitate the hydroarylation/o‐arylation process in the same pot affording the carbazole/oxepine fused N‐heterocycles. The reaction proceeded with similar efficiency on gram scale.magnified image