Rhodium(III)‐Catalyzed ortho C?H Heteroarylation of (Hetero)aromatic Carboxylic Acids: A Rapid and Concise Access to π‐Conjugated Poly‐heterocycles

Rh^III‐catalyzed oxidative C H/C H cross‐coupling between (hetero)aromatic carboxylic acids and various heteroarenes has been accomplished to construct highly functionalized ortho‐carboxy‐substituted bi(hetero)aryls. The use of a carboxy group as the directing group obviates tedious steps for installation and removal of extra directing groups, and enables a facile one‐step synthesis of ortho‐carboxy bi(hetero)aryls. The method provides opportunities for rapid assembly of a library of important fluorene and coumarin‐type poly‐heterocycles through intramolecular electrophilic substitution or oxidative lactonization. As illustrative examples, the strategy developed herein greatly streamlines accesses to a variety of appealing polyheterocycles such as DTPO (5H‐dithieno[3,2‐b:2′,3′‐d]pyran‐5‐one), CPDTO (cyclopentadithiophen‐4‐one), and indenothiophenes.     

Light‐Induced CH Arylation of (Hetero)arenes by In Situ Generated Diazo Anhydrides

Diazo anhydrides (Ar?N?N?O?N?N?Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst‐free C?H arylation methodology for the preparation of bi(hetero)aryls by the one‐pot reaction of anilines with tert‐butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate. The generated aryl radical then efficiently reacts with a (hetero)arene to form the desired bi(hetero)aryls producing only nitrogen, water, and tert‐butanol as byproducts. The scope of the reaction for several substituted anilines and (hetero)arenes was investigated. A continuous‐flow protocol increasing selectivity and safety has been developed enabling the experimentally straightforward preparation of a variety of substituted bi(hetero)aryls within 45 min of reaction time.     

Regioselective Ruthenium‐Catalyzed Carbonylative Direct Arylation of Five‐Membered and Condensed Heterocycles

A ruthenium‐catalyzed carbonylative C?H bond arylation process for the three‐component synthesis of complex aryl–(hetero)aryl ketones in an aqueous solution has been developed. By exploiting the ortho‐activating effect of nitrogen‐containing directing groups, a regioselective, successive twofold C(sp²)?C(sp²) bond formation has been achieved. This straightforward catalytic process provides access to versatile products prevalent in multiple bioactive compounds and supplies a valuable functional group for subsequent transformations.     

Nitrone Directing Groups in Rhodium(III)‐Catalyzed C−H Activation of Arenes: 1,3‐Dipoles versus Traceless Directing Groups

Functionalizable directing groups (DGs) are highly desirable in C?H activation chemistry. The nitrone DGs are explored in rhodium(III)‐catalyzed C?H activation of arenes and couplings with cyclopropenones. N‐tert‐butyl nitrones bearing a small ortho substituent coupled to afford 1‐naphthols, where the nitrone acts as a traceless DG. In contrast, coupling of N‐tert‐butyl nitrones bearing a bulky ortho group follows a C?H acylation/[3+2] dipolar addition pathway to give bicyclics. The coupling of N‐arylnitrones follows the same acylation/[3+2] addition process but delivers different bicyclics.     

Chiral Cp‐Rhodium(III)‐Catalyzed Asymmetric Hydroarylations of 1,1‐Disubstituted Alkenes

Metal‐catalyzed functionalizations at the ortho position of a directing group have become an efficient bond‐forming strategy. A wide range of transformations that employ Cp*Rh^III catalysts have been described, but despite their synthetic potential, enantioselective variants that use chiral versions of the Cp* ligand remain scarce (Cp*=pentamethyl cyclopentadienyl). Cyclopentadienyl compounds with an atropchiral biaryl backbone are shown to be suitable ligands for the efficient intramolecular enantioselective hydroarylation of aryl hydroxamates. Dihydrofurans that bear methyl‐substituted quaternary stereocenters are thus obtained by C? H functionalization under mild conditions.     

Copper/Silver‐Mediated Direct ortho‐Ethynylation of Unactivated (Hetero)aryl CH Bonds with Terminal Alkyne

A copper/silver‐mediated oxidative ortho‐ethynylation of unactivated aryl C?H bonds with terminal alkyne has been developed. The reaction uses the removable PIP directing group and features broad substrate scope, high functional‐group tolerance, and compatibility with a wide range of heterocycles, providing an efficient synthesis of aryl alkynes. This procedure highlights the potential of copper catalysts to promote unique, synthetically enabling C?H functionalization reactions that lie outside of the current scope of precious metal catalysis.     

Pd‐Catalyzed C−H Alkylation of Arenes Using PyrDipSi,a Transformable and Removable Silicon‐Tethered Directing Group

An efficient Pd‐catalyzed ortho‐C?H alkylation reaction of arenes using a transformable and removable Si‐tethered pyridyldiisopropylsilyl (PyrDipSi) directing group has been developed. In addition, the PyrDipSi directing group allows for an efficient sequential double‐fold C?H alkylation/oxygenation of arenes to produce meta‐alkylated phenols. This directing group can easily be removed or converted into valuable functionalities, such as aryl, iodo, boronic ester, or phenol.     

Ruthenium Catalyzed C−H Acylmethylation of N‐Arylphthalazine‐1,4‐diones with α‐Carbonyl Sulfoxonium Ylides: Highway to Diversely Functionalized Phthalazino‐fused Cinnolines

A direct ortho‐Csp²‐H acylmethylation of 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with α‐carbonyl sulfoxonium ylides is achieved through a Ru^II‐catalyzed C?H bond activation process. The protocol featured high functional group tolerance on the two substrates, including aryl‐, heteroaryl‐, and alkyl‐substituted α‐carbonyl sulfoxonium ylides. Thereafter, 2‐(ortho‐acylmethylaryl)‐2,3‐dihydrophthalazine‐1,4‐diones were used as potential starting materials for the expeditious synthesis of 6‐arylphthalazino[2,3‐a]cinnoline‐8,13‐diones and 5‐acyl‐5,6‐dihydrophthalazino[2,3‐a]cinnoline‐8,13‐diones under Lawesson's reagent and BF₃?OEt₂ mediated conditions, respectively. Of these, the BF₃?OEt₂‐mediated cyclization proceeded in DMSO as a solvent and a methylene source via dual C?C and C?N bond formations.     

Carboxy Group as a Remote and Selective Chelating Group for C−H Activation of Arenes

The first example of carboxy group assisted, remote‐selective C(sp²)?H activation with a Pd^II catalyst has been developed and proceeds through a possible κ² coordination of the carboxy group, thus suppressing the ortho‐C?H activation through κ¹ coordination. Besides meta‐C?H olefination, direct meta‐arylation of hydrocinnamic acid derivatives with low‐cost aryl iodides has been achieved for the first time. These findings may motivate the exploration of novel reactivities of the carboxy assisted C?H activation reactions with intriguing selectivities.     

Rhodium(III)‐Catalyzed Selective ortho‐Olefinations of N‐Acyl and N‐Aroyl Sulfoximines by CH Bond Activation

Two new rhodium‐catalyzed oxidative couplings between sulfoximine derivatives and alkenes by regioselective C?H activation, affording ortho‐olefinated (Heck‐type) products, are reported. A synthetic application of the ortho‐alkenylated products into the corresponding cyclic derivatives has been demonstrated, and a mechanistic rational for the rhodium catalysis is presented.     

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)‐C(sp³) bonds.     

Selective ortho‐Functionalization of Adamantylarenes Enabled by Dispersion and an Air‐Stable Palladium(I) Dimer

Contrary to the general belief that Pd‐catalyzed cross‐coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C?Br ortho to an adamantyl group is as favored as the corresponding adamantyl‐free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C?Br ortho to an adamantyl group, even if challenged with competing non‐hindered C?OTf or C?Cl sites. The method makes use of an air‐stable Pd^I dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5–30 min.     

Palladium(II)‐Catalyzed meta‐CH Olefination: Constructing Multisubstituted Arenes through Homo‐Diolefination and Sequential Hetero‐Diolefination

Divinylbenzene derivatives represent an important class of molecular building blocks in organic chemistry and materials science. Reported herein is the palladium‐catalyzed synthesis of divinylbenzenes by meta‐C? H olefination of sulfone‐based arenes. Successful sequential olefinations in a position‐selective manner provided a novel route for the synthesis of hetero‐dialkenylated products, which are difficult to access using conventional methods. Additionally, 1,3,5‐trialkenylated compounds can be generated upon successful removal of the directing group.     

Condensation products of 1‐aryl‐4‐carboxy‐ 2‐ pyrrolidinones with o‐diaminoarenes,o‐aminophenol,and their structural studies

A series of 2‐substituted benzimidazoles, benzoxazoles were synthesized by the condensation reactions of 1‐aryl‐4‐carboxy‐2‐pyrrolidinones and aromatic ortho‐diamines or ortho‐aminophenol. Alkylation of benzimidazoles with iodoalkanes led to 1‐aryl‐4‐(1‐alkyl‐1H‐benzimidazol‐2‐yl)‐2‐pyrrolidin‐ ones or 1,3‐dialkylbenzimidazolium iodides. N‐Subs‐ tituted γ‐amino acids were prepared by the hydrolysis of 1‐aryl‐4‐(1H‐benzimidazol‐2‐yl)‐2‐pyrrolidinones in sodium hydroxide solution, followed by treatment with acetic acid. The structure of the synthesized pro‐ ducts was investigated using IR and ¹H, ¹³C NMR spectra, MM2 molecular mechanics, and AM1 semi‐ empirical quantum mechanical methods. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:47–56, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20171     

Rhodium(III)‐Catalyzed CC and CO Coupling of Quinoline N‐Oxides with Alkynes: Combination of CH Activation with O‐Atom Transfer

[Cp*Rh^III]‐catalyzed C? H activation of arenes assisted by an oxidizing N? O or N? N directing group has allowed the construction of a number of hetercycles. In contrast, a polar N? O bond is well‐known to undergo O‐atom transfer (OAT) to alkynes. Despite the liability of N? O bonds in both C? H activation and OAT, these two important areas evolved separately. In this report, [Cp*Rh^III] catalysts integrate both areas in an efficient redox‐neutral coupling of quinoline N‐oxides with alkynes to afford α‐(8‐quinolyl)acetophenones. In this process the N? O bond acts as both a directing group for C? H activation and as an O‐atom donor.     

Cascade One‐Pot Synthesis of Orange‐Red‐Fluorescent Polycyclic Cinnolino[2,3‐f]phenanthridin‐9‐ium Salts by Palladium(II)‐Catalyzed C−H Bond Activation of 2‐Azobiaryl Compounds and Alkenes

Quaternary ammonium salts were synthesized in moderate to good yields through double oxidative C?H bond activation on azobenzenes. The mechanism of the highly regioselective reaction of 2‐azobiaryls with alkenes to give orange‐red‐fluorescent cinnolino[2,3‐f]phenanthridin‐9‐ium salts and 15H‐cinnolino[2,3‐f]phenanthridin‐9‐ium‐10‐ide is proposed to involve ortho C?H olefination of the 2‐azobiaryl compound with the alkene, intramolecular aza‐Michael addition, concerted metalation–deprotonation (CMD), reductive elimination, and oxidation.     

Palladium‐Catalyzed Arylation of Unactivated γ‐Methylene C(sp3)H and δ‐CH Bonds with an Oxazoline‐Carboxylate Auxiliary

A palladium‐catalyzed arylation of unactivated γ‐methylene C(sp³)?H and remote δ‐C?H bonds by using an oxazoline‐carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline‐type auxiliary can be removed under acidic conditions.     

Cyclopenta[b]annulation of Heteroarenes by Organocatalytic γ′[C(sp3)−H] Functionalization of Ynones

A new approach for the cyclopenta[b]annulation of heteroarenes through metal‐free and directing‐group‐free γ′[C(sp³)?H] functionalization and intramolecular hydroalkylation of ynones has been developed. In an unprecedented event, nucleophilic addition of an organophosphine to the designed ynones triggers γ′[C(sp³)?H] functionalization, leading to the formation of heteroaryl‐based ortho‐quinodimethane (oQDM) intermediates that undergo carbocyclization to provide cyclopentannulated heteroarenes in good yields and excellent stereoselectivities. Deuterium‐labeling experiments substantiated the proposed reaction mechanism as well as the speculated epimerization.     

Room‐Temperature ortho‐Alkoxylation and ‐Halogenation of N‐Tosylbenzamides by Using Palladium(II)‐Catalyzed CH Activation

The N‐tosylcarboxamide group can direct the room‐temperature palladium‐catalyzed C?H alkoxylation and halogenation of substituted arenes in a simple and mild procedure. The room‐temperature stoichiometric cyclopalladation of N‐tosylbenzamide was first studied, and the ability of the palladacycle to react with oxidants to form C?X and C?O bonds under mild conditions was demonstrated. The reaction conditions were then adapted to promote room‐temperature ortho‐alkoxylations and ortho‐halogenations of N‐tosylbenzamides using palladium as catalyst. The scope and limitation of both alkoxylations and halogenations was studied and the subsequent functional transformation of the N‐tosylcarboxamide group through nucleophilic additions was evaluated. This methodology offers a simple and mild route to diversely functionalized arenes.     

MnI/AgI Relay Catalysis: Traceless Diazo‐Assisted C(sp2)–H/C(sp3)–H Coupling to β‐(Hetero)Aryl/Alkenyl Ketones

An unprecedented Mn^I/Ag^I‐relay‐catalyzed C(sp²)?H/C(sp³)?H coupling of (vinyl)arenes with α‐diazoketones is reported, wherein the diazo group was exploited as a traceless auxiliary for control of regioselectivity. Challenging β‐(hetero)aryl/alkenyl ketones were obtained through this operationally simple approach. The cascade process merges denitrogenation, carbene rearrangement, C?H activation, and hydroarylation/hydroalkenylation. The robustness of this method was demonstrated at preparative scale and applied to late‐stage diversification of natural products.