Divergent Reactivity in Palladium‐Catalyzed Annulation with Diarylamines and α,β‐Unsaturated Acids: Direct Access to Substituted 2‐Quinolinones and Indoles

A palladium‐catalyzed C?H activation strategy has been successfully employed for exclusive synthesis of a variety of 3‐substituted indoles. A [3+3] annulation for synthesizing substituted 2‐quinolinones was recently developed by reaction of α,β‐unsaturated carboxylic acids with diarylamines under acidic conditions. In the present work, an analogous [3+2] annulation is achieved from the same set of starting materials under basic conditions to generate 1,3‐disubstituted indoles exclusively. Mechanistic studies revealed an ortho‐palladation–π‐coordination–β‐migratory insertion–β‐hydride elimination reaction sequence to be operative under the reaction conditions.     

Palladium‐Catalyzed [3+3] Annulation between Diarylamines and α,β‐Unsaturated Acids through CH Activation: Direct Access to 4‐Substituted 2‐Quinolinones

A C?H activation strategy has been successfully employed for the high‐yielding synthesis of a diverse array of 4‐substituted 2‐quinolinone species by a palladium‐catalyzed dehydrogenative coupling involving diarylamines. This intermolecular annulation approach incorporates readily available α,β‐unsaturated carboxylic acids as the coupling partner by suppressing the facile decarboxylation. Based on preliminary mechanistic studies, a reaction sequence is proposed, involving ortho palladation, π‐coordination, β‐migratory insertion, and β‐hydride elimination.     

Carboxylic Acids as Traceless Directing Groups for the Rhodium(III)‐Catalyzed Decarboxylative CH Arylation of Thiophenes

A rhodium(III)‐catalyzed carboxylic acid directed decarboxylative C? H/C? H cross‐coupling of carboxylic acids with thiophenes has been developed. With a slight adjustment of the reaction conditions based on the nature of the substrates, aryl carboxylic acids with a variety of substituents could serve as suitable coupling partners, and a broad variety of functional groups were tolerated. This method provides straightforward access to biaryl scaffolds with diverse substitution patterns, many of which have conventionally been synthesized through lengthy synthetic sequences. An illustrative example is the one‐step gram‐scale synthesis of a biologically active 3,5‐substituted 2‐arylthiophene by way of the current method.     

Synthesis and Cyclization of 8‐Formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic Acids

A facile synthesis of a series of new quinoline‐8‐carbaldehyde compounds, namely 8‐formyl‐2‐(phenoxymethyl)quinoline‐3‐carboxylic acids ( 4a – 4h ) and 13‐oxo‐6,13‐dihydro[1]benzoxepino[3,4‐b]quinoline‐8‐carbaldehyde ( 5a – 5g ) is described, involving the one‐pot synthesis reaction of ethyl 2‐(chloromethyl)‐8‐formylquinoline‐3‐carboxylate ( 3 ) with substituted phenols followed by the intramolecular cyclization reaction via the treatment with polyphosphoric acid (PPA). Quinoline‐8‐carbaldehydes 4a – 4h and 5a – 5g are novel and their structures were supported by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis.     

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

Pd^II‐catalyzed enantioselective C(sp³)?H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.     

Cobalt‐Catalyzed C8‐Dienylation of Quinoline‐N‐Oxides

An efficient Cp*Co^III‐catalyzed C8‐dienylation of quinoline‐N‐oxides was achieved by employing allenes bearing leaving groups at the α‐position as the dienylating agents. The reaction proceeds by Co^III‐catalyzed C?H activation of quinoline‐N‐oxides and regioselective migratory insertion of the allene followed by a β‐oxy elimination, leading to overall dienylation. Site‐selective C?H activation was achieved with excellent selectivity under mild reaction conditions, and 30 mol % of a NaF additive was found to be crucial for the efficient dienylation. The methodology features high stereoselectivity, mild reaction conditions, and good functional‐group tolerance. C8‐alkenylation of quinoline‐N‐oxides was achieved in the case of allenes devoid of leaving groups as coupling partners. Furthermore, gram‐scale preparation and preliminary mechanistic experiments were carried out to gain insights into the reaction mechanism.     

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.     

Ligand‐Enabled PdII‐Catalyzed Iterative γ‐C(sp3)−H Arylation of Free Aliphatic Acid

C?H functionalization of aliphatic carboxylic acids without attaching exogenous auxiliary has been so far limited at the proximal β‐position. In this work, we demonstrate a ligand enabled palladium catalyzed first regioselective distal γ‐C(sp3)?H functionalization of aliphatic carboxylic acids without incorporating an exogenous directing group. Aryl iodides containing versatile functional groups including complex organic molecules are well tolerated with good to excellent yields during the γ‐C(sp3)?H arylation reaction. Interestingly, weak coordination of carboxylate group can be further extended for sequential hetero di‐arylation. Application of the protocol has been showcased by synthesizing substituted α‐tetralone. Mechanistic investigations have been carried out to shed light on the reaction pathway.     

Ruthenium(II)‐Catalyzed CH Functionalizations with Allenes: Versatile Allenylations and Allylations

Ruthenium(II)‐catalyzed direct C?H functionalization of aromatic compounds with allenes was achieved under exceedingly mild reaction conditions to yield trisubstituted allenes. The reactions of N‐methoxybenzamides proceeded smoothly in an isohypsic fashion at ambient temperature with high chemo‐ and regioselectivity, thereby providing a versatile means of accessing trisubstituted allenes. Detailed mechanistic studies were suggestive of a kinetically relevant C?H metalation step, which occurs by the assistance of a carboxylate moiety; this also set the stage for unprecedented C?H allylations with removable directing groups in a step‐economical fashion.     

Palladium‐Catalyzed Decarboxylative γ‐Arylation for the Synthesis of Tetrasubstituted Chiral Allenes

An enantiospecific palladium‐catalyzed decarboxylative coupling of acyclic β,γ‐alkynoic acids with various aryl iodides to chiral tetrasubstituted allenes is described. The coupling reaction comprises a decarboxylative γ‐palladation of α,α‐disubstituted carboxylic acids to provide the tetrasubstituted allenes with complete point‐to‐axial chirality transfer in excellent yields.     

Synthesis of Isoindolo[2,1‐a]quinazoline‐5,11‐dione Derivatives via the Reductive One‐Pot Reaction of N‐Substituted 2‐Nitrobenzamides and 2‐Formylbenzoic Acids

Various isoindolo[2,1‐a]quinazoline‐5,11‐dione derivatives 3 were synthesized in good yields by means of the reductive reaction of N‐substituted 2‐nitrobenzamides 1 and 2‐formylbenzoic acids 2 in the presence of SnCl₂?2 H₂O under reflux in EtOH (Scheme, Table). The procedure needed two steps, the reduction of the nitro group of the 2‐nitrobenzamide and ring closure by nucleophilic addition of the NH₂ group to both the formyl and carboxylic acid C?O groups.     

Iridium‐Catalyzed Annulation Reactions of Thiophenes with Carboxylic Acids: Direct Evidence for a Heck‐type Pathway

The functionalization of thiophenes is a fundamental and important reaction. Herein, we disclose iridium‐catalyzed one‐pot annulation reactions of (benzo)thiophenes with (hetero)aromatic or α,β‐unsaturated carboxylic acids, which afford thiophene‐fused coumarin‐type frameworks. Dearomatization reactions of 2‐substituted thiophenes with α,β‐unsaturated carboxylic acids deliver various thiophene‐containing spirocyclic products. The occurrence of two interconnected reactions provides direct evidence for a Heck‐type pathway. The mechanistic scenario described herein is distinctly different from the S_EAr and concerted metalation–protodemetalation (CMD) pathways encountered in the well‐described oxidative C?H/C?H cross‐coupling reactions of thiophenes with other heteroarenes.     

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

Indoles are ubiquitous structures that are found in natural products and biologically active molecules. The synthesis of indoles and indole‐involved synthetic methodologies in organic chemistry have been receiving considerable attention. Indole‐N‐carboxylic acids and derived indole‐N‐carboxamides are intriguing compounds, which have been widely used in organic synthesis, especially in multicomponent reactions and C?H functionalization of indoles. This Minireview summarizes the advances of reactions involving indole‐N‐carboxylic acids and indole‐N‐carboxamides in organic chemistry, and discusses the synthetic potential and perspective of this field.     

Synthesis and molecular structures of 1‐boracyclopent‐2‐enes

The reaction of 1‐silyl‐1‐borylalkenes with alkyn‐1‐yltin compounds affords borol‐2‐enes, organometallic‐substituted allenes, mixtures thereof or even more complex mixtures with buta‐1,3‐dienes, depending on the third substituent at the C?C bond (Bu or Ph), on the number of Si? Cl functions (two or three) and the nature of the alkyn‐1‐yltin compound. Six new borol‐2‐enes were isolated in pure state, and two of them were characterized by X‐ray structural analysis. The solution‐state structures of all major products were clearly established by multinuclear magnetic resonance methods (¹H, ¹¹B, ¹³C, ²⁹Si, ¹¹⁹Sn NMR). Copyright © 2009 John Wiley & Sons, Ltd.     

Stereoselective Synthesis of 1,3‐Diaminotruxillic Acid Derivatives: An Advantageous Combination of CH‐ortho‐Palladation and On‐Flow [2+2]‐Photocycloaddition in Microreactors

The stereoselective synthesis of ε‐isomers of dimethyl esters of 1,3‐diaminotruxillic acid in three steps is reported. The first step is the ortho‐palladation of (Z)‐2‐aryl‐4‐aryliden‐5(4H)‐oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho‐C?H bond of the 4‐arylidene ring in carboxylic acids. The second step is the [2+2]‐photocycloaddition of the C?C exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho‐palladated cyclobutanes 3 . This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the ε‐1,3‐diaminotruxillic acid derivatives as single isomers.     

Decarboxylative Conjunctive Cross‐coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross‐coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross‐coupling cascade of vinyl boronic esters. Excellent functional‐group tolerance is displayed, and application of a range of carboxylic acids, including secondary α‐amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross‐coupling was also applied to the synthesis of sedum alkaloids.     

Bottom‐up Construction of π‐Extended Arenes by a Palladium‐Catalyzed Annulative Dimerization of o‐Iodobiaryl Compounds

A straightforward method was developed for construction of aromatic compounds with a triphenylene core. The method involves Pd‐catalyzed annulative dimerization of o‐iodobiaryl compounds by double C?I and C?H bond cleavage steps. Simple reaction conditions are needed, requiring neither a ligand nor an oxidant, and the reaction tolerates a wide range of coupling partners without compromising efficiency or scalability. Significantly, the tetrachloro‐substituted synthon, 1,6,11‐trichloro‐4‐(4‐chlorophenyl)triphenylene, can be generated and used to prepare a series of fully fused, small graphene nanoribbons by a late‐stage arylation with arylboronic acids and a subsequent Scholl reaction. The synthetic strategy enables bottom‐up access to extended π‐systems in a controlled manner.     

Rhodium(III)/Copper(II)‐Promoted trans‐Selective Heteroaryl Acyloxylation of Alkynes: Stereodefined Access to trans‐Enol Esters

Enol esters are versatile synthetic building blocks which can be elaborated by a wide variety of transformations. The classical synthesis by O‐selective enolate acylation often hampers control of the E/Z selectivity with highly substituted substrates. A rhodium(III)/copper(II)‐mediated process is reported to provide tetrasubstituted enol esters in a trans‐selective fashion. Overall, the reaction consists of a heteroaryl acyloxylation of alkynes. The process is initiated by a rhodium(III)‐catalyzed C2‐selective activation of electron‐rich heteroarenes, such as benzofuran, furan, and thiophene. Upon addition across an alkyne, a transmetalation to copper(II) enables reductive C? O bond formation. The transformation allows the three‐component couplings of heteroarenes, alkynes, and carboxylic acids. Application of the method in the functionalization of bioactive furocoumarin natural products is also described.     

Copper‐Mediated Aminoquinoline‐Directed Radiofluorination of Aromatic C−H Bonds with K18F

A Cu‐mediated ortho‐C?H radiofluorination of aromatic carboxylic acids that are protected as 8‐aminoquinoline benzamides is described. The method uses K¹⁸F and is compatible with a wide range of functional groups. The reaction is showcased in the high specific activity automated synthesis of the RARβ2 agonist [¹⁸F]AC261066.     

Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single‐electron reduction of an α‐boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α‐amino, α‐oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron‐containing molecules of potential biological importance.