Recent Advances in Palladium-Catalyzed Oxidative Couplings in the Synthesis/Functionalization of Cyclic Scaffolds Using Molecular Oxygen as the Sole Oxidant

Abstract

Over the past years, Pd(II)-catalyzed oxidative couplings have enabled the construction of molecular scaffolds with high structural diversity via C–C, C–N and C–O bond-forming reactions. In contrast to the use of stoichiometric amounts of more common oxidants, such as metal salts (Cu and Ag) and benzoquinone derivatives, the use of molecular oxygen for the direct or indirect regeneration of Pd(II) species presents itself as a more viable alternative in terms of economy and sustainability. In this review, we describe recent advances on the development of Pd-catalyzed oxidative cyclizations/functionalizations, where molecular oxygen plays a pivotal role as the sole stoichiometric oxidant.

1 Introduction

2 Oxidative C–C and C–Nu Coupling

2.1 Intramolecular Oxidative C–Nu Heterocyclization Reactions

2.1.1 C–H Activation

2.1.2 Wacker/Aza-Wacker-Type Cyclization

2.1.3 Tandem Wacker/Aza-Wacker and Cyclization/Cross-Coupling Reactions

2.2 Intermolecular Oxidative C–Nu Heterocoupling Reactions

2.3 Intramolecular Oxidative (C–C) Carbocyclization Reactions

2.4 Intermolecular Oxidative C–C Coupling Reactions

2.4.1 Cyclization Reactions

2.4.2 Cross-Coupling Reactions

2.4.3 Homo-Coupling Reactions

3 Aerobic Dehydrogenative Coupling/Functionalization

4 Oxidative C–H Functionalization

5 Summary

Biographical Sketches

Amanda Aline Barboza received her M.Sc. degree in 2019 from the Federal University of São Carlos (Brazil), and she is currently a Ph.D. student at the same university under the supervision of Professor Dr. Marco Ferreira. Her research interests encompass the synthesis of organic compounds by means of metal catalysis and the use of statistical modeling in catalysis to understand and predict organic reactions and new catalysts.

Juliana Arantes Dantas received her M.Sc. degree from the Federal University of São Carlos (Brazil) in 2018 under the supervision of Professor Arlene G. Corrêa. In 2019, she began her Ph.D. studies at the same university under the supervision of Professor Dr. Marco Ferreira. Her research interests focus on the development of transition-metal catalysis and photocatalysis.

Attilio Chiavegatti received his degree in chemistry from the Federal University of São Carlos (Brazil) in 2020. In the following year he started his Ph.D. studies on olefin metathesis reactions at the same university under the supervision of Professor Dr. Marco ­Ferreira. His research interests involve computational studies of reaction mechanisms and the use of statistical modeling in organic chemistry reactions.

Mateus Oliveira Costa received his B.Sc. degree in chemistry from the Federal University of São Carlos (Brazil) in 2019. He has since been pursuing his M.Sc. degree in chemistry under the supervision of Prof. Dr. Marco Ferreira. His areas of interest in research include cobalt-catalyzed oxidative biomass valorization and computational studies of organic chemistry reactions.

Guilherme Augusto de Melo Jardim obtained his Ph.D. in 2018 at the Federal University of Minas Gerais (Brazil), working on innovative methods involving C–H bond activation in the functionalization of bioactive compounds. Currently, he is a postdoctoral researcher at the Federal University of São Carlos (Brazil). His research interests are focused on catalysis involving Pd atoms in both thermal and photochemical domains.

Marco Antonio Barbosa ­Ferreira received his B.S. degree in chemistry from the University of São Paulo (Brazil) in 2005, before obtaining his M.Sc. in 2008 and his Ph.D. in 2012 at the University of Campinas (Brazil) with Luiz Carlos Dias. In 2013 he joined the faculty of the Federal University of São Carlos (Brazil). He then moved to the University of Utah (USA) in 2018 for postdoctoral work with Matthew S. Sigman, before returning to the Federal University of São Carlos in 2019. His research group has focused on the development of new synthetic methodologies and reaction mechanisms.

Introduction

The selective functionalization of petroleum-derived feedstocks constitutes the industrial base by which we establish our modern society, allowing the transformation of simple organic molecules into value-added products. Although the use of fossil feedstocks is economically advantageous due to their low processing cost, a global movement towards a more sustainable society has guided the industry and the scientific community in recent decades, resulting in the use of renewable feedstocks and the development of greener and more sustainable reactions. In particular, oxidation reactions represent a pivotal class of organic transformations for the conversion of unfunctionalized hydrocarbons,[1] and even today present significant challenges regarding the selectivity and generation of large quantities of by-products derived from the use of stoichiometric oxidants. In this regard, Pd(II)-catalyzed homogeneous oxidative reactions have emerged as a highly attractive approach to functionalize organic molecules, allowing diversity in bond formation and exceptional selectivity.[2] However, in order to regenerate the Pd(II) species at the end of the process, Pd(II)-catalyzed oxidative reactions require the use of a stoichiometric oxidant, such as Cu(II), Ag(I), benzoquinone or O₂, to oxidize the generated Pd(0) species.[3] These processes have been termed ‘oxidase’-type reactions, inspired by ‘oxidase’-type enzymes that oxidize substrates without transfer of an oxygen atom (Scheme [1]).[4] The Wacker reaction, which involves the oxidation of ethylene to acetaldehyde,[5] exemplifies the first industrial application of homogeneous catalysis using organopalladium chemistry, being one of the most important examples of this reaction class.

Air is clearly a convenient choice as a terminal oxidant, considering its abundance and the oxidation potential of molecular oxygen. The use of a stoichiometric amount of O₂ as a terminal oxidant and proton acceptor has enormous advantages due to the sustainability associated with the formation of environmentally benign by-products like water and hydrogen peroxide.[6] However, under aerobic oxidation conditions and in the absence of a co-catalyst, a significant challenge is associated with the propensity of Pd(0) to precipitate into its inactive metallic form.[7] [8] During recent decades, enhanced stability of Pd(0) has been observed by using molecular sieves[9] and ancillary ligands.[10] Considerable advances have been made in this field in the past decades, focusing on the development of more environmentally friendly Pd-catalyzed aerobic transformations. The comprehensive reviews of Stahl in 2004[4] and 2018,[10] and that of Gligorich and Sigman[11] in 2009, surveyed oxidatively stable ligands allied with mechanistic studies, giving directions on how to improve the catalysts. Moreover, recent related but not comprehensive reviews describe the application of green oxidants based on Pd.[3] [12] In this review, the approach is to some extent different, surveying recent reactions involving Pd-catalyzed oxidative cyclizations and functionalizations of cyclic compounds, where molecular oxygen plays a pivotal role as the sole stoichiometric oxidant. Our review covers recent publications from 2014 until now, where most of the selected work dates from 2017 to 2021. Whenever possible, we have emphasized mechanistic aspects and limitations associated with the transformations.

Oxidative C–C and C–Nu Coupling

Oxidative couplings are considered an emerging and powerful alternative for the formation of new bonds, as well as representing a complementary approach to conventional cross-coupling reactions for the generation of diverse and complex scaffolds.[13] These C–C and C–Nu (heteroatom) cross-coupling processes can occur in a selective manner, with no activated bonds, representing an important advance towards more sustainable processes.

Intramolecular Oxidative C–Nu Heterocyclization Reactions

C–H Activation

Direct activation of C–H bonds is a straightforward oxidative coupling approach that can be utilized to access heterocyclic compounds with diverse frameworks.[14] In this sense, cross-dehydrogenative coupling (CDC) stands out for its operability and atom economy, with valuable examples reported in the literature for the synthesis of polyhetero­cyclic structures.[15] In 2017, the Das group presented a divergent methodology employing CDC to obtain pyran-based heterocycles (Scheme [2]).[16] From common starting materials and using an oxidative palladium-catalyzed reaction, a chemoselective switch by combining intramolecular C–H/C–H or C–H/N–H oxidative couplings has been successfully developed, leading to the formation of C–C or C–N bonds. Both reactions employed catalytic amounts of Pd(OAc)₂ in basic medium and utilized O₂ as the terminal oxidant, making possible the construction of pyran derivatives through the formation of C–N bonds. Two selected examples of naturally occurring carbazoles, clauraila C (74%) and a pentacyclic carbazole (79%), were efficiently synthesized.[17] Based on experimental results, the proposed mechanism for these two reactions differs at the beginning of the catalytic cycle, when palladium can favorably coordinate with the chromene ring in the presence of p-TsOH (C–C coupling), or coordinates with NHTs in the presence of K₂CO₃ (C–N coupling). A possible explanation for this difference in selectivity has been suggested and involves the in situ formation of reactive palladium mono- or bis-tosylate species from Pd(OAc)₂. Both conditions seem to benefit from the presence of the polar coordinating solvent DMF, which promotes an efficient and direct dioxygen-coupled turnover (Scheme [2]).

In 2019, Youn and co-workers demonstrated an aerobic palladium-catalyzed regioselective C–H activation strategy involving N-Ts-2-amino-3′-hydroxybiaryl substrates (Scheme [3]).[18] In this approach, the authors explored a dual directing group strategy to achieve a sterically hindered ­C–H bond (C2 position), providing a diverse range of ­1-hydroxy­carbazoles in an unusual and highly regioselective fashion, mainly attributed to the presence of the hydroxy moiety as a secondary directing group. This protocol represents an advance in the synthesis of 1-oxygenated carbazole alkaloids, with the benefit of a practical and sustainable approach, using the combination of a bidentate bipyridyl ligand and ambient air as the terminal oxidant of the Pd catalyst. The effectiveness of the hydroxy group was inferred by applying other potential secondary directing groups [e.g., -OMe, -NHTs, -NHAc, -O(2-Py), -OSi(OH)tBu₂], with the coupling being conducted exclusively or mostly at the less sterically hindered position. The proposed reaction mechanism proceeds through chelation of Pd(II) with both the hydroxy and sulfonamide groups via dual directing-group-assisted C–H activation. A kinetic isotope effect (KIE, k _H/k _D = 2.2) related to an intermolecular competition experiment, as well as H/D exchange, suggested irreversible C–H bond cleavage as the rate-determining step (Scheme [3]).

Wacker/Aza-Wacker-Type Cyclization

A methodology reporting access to alkylidene γ-lactams from N-sulfonylalkenylamides was presented by Poli and Oble in 2016, proceeding by way of a new aerobic approach to aminopalladation reactions via a sequential proxicyclic β-hydride elimination (Scheme [4]).[19] The transformation was studied mechanistically by DFT calculations, together with deuterium-labeling experiments, indicating that the cyclization process occurs via an anti-aminopalladation event. A positive effect on the yield was observed using chloride ions, with the hypothesis being that these anions increase the electrophilic character of the Pd-alkene complex. The use of triphenylphosphine was claimed to avoid the coordination of the sulfonyl oxygen, allowing the proxicyclic dehydropalladation in sequence, a step observed previously as inhibited. Nevertheless, an investigation of the stability of triphenylphosphine under aerobic conditions was not assessed (Scheme [4]).

Recently, our group reported a significant contribution towards the aerobic Wacker-type cycloisomerization protocol for the synthesis of 3-carbonyl trisubstituted furans by using 2-alkenyl-1,3-dicarbonyl scaffolds, an underexplored substrate in this approach, and avoiding the use of stoichiometric amounts of oxidants and strong acid additives (Scheme [5]).[20] These mild conditions demonstrated good functional group tolerance and afforded good to excellent yields. In addition, a detailed study of the mechanism was carried out through DFT calculations and by kinetic and multivariate linear regression (MLR) analysis. Some important findings from the results indicated that a neutral and an anionic path could be conducted in a parallel manner, and that the rate-determining step was related to the deprotonation event that occurs through AcO^– coordination in the complex (KIE, k _H/k _D = 1.7). Interestingly, while the nucleo­palladation occurs via anti-attack in a neutral path, the anionic path preferentially proceeds in syn fashion. The MLR analysis indicated the cooperative impact of the electronic and steric parameters in the reaction outcome, with product decomposition via hydrolysis of the ester functionality (detected by GC-MS), or steric effects on intramolecular oxo-palladation transitions states (Scheme [5]).

Tandem Wacker/Aza-Wacker and Cyclization/­Cross-Coupling Reactions

A tandem cyclization of unsaturated anilides via palladium catalysis under oxidative aerobic conditions was reported by Yang and co-workers through the development of enantioselective protocols employing quinox ligands (Scheme [6]).[21] By exploring different chiral bidentate dinitrogen classes of ligands (quinox, pyrox, BOX, and sparteine), a new protocol was developed for the synthesis of pyrrolizidines using aliphatic alkenylamides, a less rigid molecule with less acidity in the N–H bond than the previously used unsaturated anilides, and (S,S)-diPh-pyrox-type ligands.[22] The formation of C=C double bonds in some cyclized products were not selective in several cases due to subsequent β-elimination/H-insertion equilibria, leading the authors to adopt a sequential hydrogenation step and simplifying product analysis. By studying this Pd(TFA)₂/(S,S)-diPh-pyrox catalytic system, the authors concluded through deuterium experiments and DFT transition state calculations that the anti-aminopalladation occurs preferentially (Scheme [6]).

In 2017, Yang and co-workers demonstrated a new protocol to synthesize indolizidine and azacyclic derivatives, in addition to pyrrolizidines, in high yields through two distinct sets of conditions, varying the source of palladium and the base (Scheme [7]).[23] In both protocols, the oxidative conditions benefited from using pyridine as the ligand. The stereochemistry observed in the products when 1,2-disubstituted alkenes were employed implies that the aminopalladation occurs in a highly syn-selective fashion, whereas the opposite was observed in the previous work[22] in which an anti-aminopalladation event was observed. This difference was proposed to be due to the different natures of the ligands under the two sets of reaction conditions (Scheme [7]).[23]

A dearomatizing 2,5-oxyarylation of diene-like rings via aerobic palladium-catalyzed oxidative coupling conditions was successfully implemented by Yin and collaborators in 2016 (Scheme [8]).[24] Applying furans as diene precursors and using O₂ as the sole oxidant and phenanthroline as the ligand, a wide range of spiroacetals was synthesized diastereoselectively through 2,5-oxyarylation with arylboronic acids as the reaction partners. The proposed mechanism begins with an electrophilic palladation to form a complex prone to undergo an intramolecular acetalization reaction with the terminal OH moiety. In sequence, transmetalation and reductive elimination steps occur to afford the product and release the Pd(0) that is regenerated by O₂ as the terminal oxidant. This protocol represents an advance in the synthesis of biologically important frameworks, and it has also encouraged the design of other dearomatizing transformations of diene-type rings, as shown in Schemes 9 and 10.

In 2017, the same group reported another similar advance (Scheme [9]).[25] In this new protocol, the authors described a variation of their previous report,[24] presenting a dearomatizing alkoxydiarylation to access polysubstituted oxabicyclic compounds. To achieve this goal, the authors improved the starting materials by adding an aryl group at the C5 position and thus suppressed the 2,5-oxyarylation. Efforts to include an alkyl substituent at this position failed in most examples. The process succeeded in the diastereoselective synthesis of tetrahydrofuro[3,2-b]furans and also for the synthesis of hexahydrofuro[3,2-b]furans derivatives, just by adding a step, in a one-pot strategy. Divided into 3 paths, the proposed mechanism starts with electrophilic palladation (path I), followed by O-allylation at the 3-position of the furan and deprotonation to form a fused ring. This then undergoes transmetalation and reductive elimination of Pd(0), which is itself oxidized by O₂. The newly formed compound enters path II, following similar steps as the first cycle but now the addition of a second Ar group occurs at the 4-position. The steps represented in path III are triggered by the presence of Na₂CO₃ in water, generating HO^– ions. The cis ring fusion enables coordination of Pd(II) at the less hindered face of the double bond. Next, attack of HO^– occurs on the opposite side, forming the hemiacetal after the protonation, which is prone to isomerization to form the stable thermodynamic product, thus explaining the observed stereochemistry (Scheme [9]).

In 2018, Yin and co-workers presented a new version of this previously presented dearomatization of furans, but this time involving N-[3-(2-furanyl)propyl]-p-toluenesulfonamide substrates through 2,5-aminoarylations and direct α-arylation of furan rings (Scheme [10]).[26] In this new methodology, the authors presented the possibility of forming unsaturated N,O-spiroacetals. The proposed mechanism was based on control experiments and previous work. It has been suggested that the reaction proceeds through a path involving acetalization, transmetalation, and then reductive elimination, releasing the N,O-spiroacetals and Pd(0), which is oxidized to Pd(II) by molecular oxygen (path I). A dearomatization/rearomatization strategy was developed to produce the 5-arylfurans, by introducing an additional cycle (path II) and simply exchanging the additive KF for KOAc. The Pd(II) is coordinated to the double bond of the newly formed spiro product, and in the presence of the KOAc base forms a π-allyl-Pd(II) intermediate. Isomerization and subsequent β-N elimination steps release the product and palladium in its active form (Scheme [10]).

In 2016, Ma and co-workers reported a novel dimerization of enediynes to construct naphthalene frameworks via a double [4+2]/oxygenative bimolecular annulation cascade catalyzed by palladium, with molecular oxygen playing a dual role in the regeneration of the catalyst and trapping the radical product in the presence of NaI (Scheme [11]).[27] This strategy uses a directing group approach to control the intrinsic cycloisomerization propensity of enediynes, incorporating a nucleophilic subunit as a trigger for the process. Homoannulation of enediyne–imides provided access to a class of symmetric naphthalenes, while crossover annulation of enediyne–imides resulted in unsymmetrical derivatives. An additional basic hydrolysis step provides dicarboxylic acids. The mechanistic proposal started with a 5-endo-dig anti-aminopalladation cyclization, followed by a double carbopalladation cascade with another molecule of the starting material or other functionalized enediynes. The sequence of 5-endo aminopalladation followed by a reductive elimination reaction releases the naphthalene derivative and Pd(0), which is regenerated by O₂. Investigations through ¹⁸O isotopic labelling and with radical scavengers revealed oxygen radical incorporation on a delocalized Kekulé-type diradical intermediate of the polyene to afford a di-oxygenated intermediate (Scheme [11]).

In 2019, Landais and Robert developed an aza-Wacker-type intramolecular double amination protocol using molecular oxygen as the sole oxidant, starting from aromatic sulfonamides containing a substituted cyclohexadiene at the ortho position (Scheme [12]).[28] Also, the proposed aza-Wacker-type protocol could furnish a pentacyclic product in a one-pot reaction by using carbamoyl sulfonamide derivatives instead of carbamates. The authors applied this methodology to the synthesis of the Aspidosperma skeleton, as shown by their route to a mossambine precursor (Scheme [12]).

Jiang and Li, in 2019, described a Pd(II)-catalyzed multicomponent cascade reaction between acetylenic oximes and aryl halides to afford 4-(thio)isoxazoles using Na₂S₂O₃ as a sulfenylation reagent in the ionic liquid [Cpmin]Cl ­under aerobic conditions (Scheme [13]).[29] The protocol presented good compatibility with different functional groups, high atom economy, and uses a mild sulfenylation reagent. The proposed mechanism consists of a trans-oxypalladation of the oxime to afford an isoxazole-Pd(II) intermediate. Next, the in situ formed organosulfur salt coordinates to palladium to give a Pd-thiosulfate intermediate. The product is finally released via SO₃ evolution by reductive elimination (Scheme [13]).

A four-component benzannulation reaction involving amines, aldehydes and 2 equivalents of a β-dicarbonyl compound was developed by Deng and Huang in 2019 (Scheme [14]).[30] This protocol employed PdCl₂ as the catalyst under solvent-free aerobic conditions, furnishing functionalized anilines in good yields. The proposed method showed good compatibility with diverse substituted anilines, benzylamines with different electronic properties, and amines bearing pyridine and thiophene. Different benzaldehydes showed good performance, including sterically crowded 4-tert-butylbenzaldehyde. A decrease in the yield was verified for alkyl amines or benzaldehydes bearing electron-donating substituents, and a limitation in the protocol was observed with the use of β-ketoamides. Based on control experiments, the proposed mechanism starts with a condensation reaction of the β-dicarbonyl compound with both the amine and the aldehyde, furnishing an enamine and an enedione, respectively. Next, these intermediates undergo a Michael addition to afford an adduct that readily coordinates to Pd(II). This coordination triggers a carbo-annulation reaction, affording the aniline product (Scheme [14]).

An important example of a tandem cyclization was reported by Chuang and co-workers in 2010 (Scheme [15]).[31] In the proposed method, the authors explored a Pd-catalyzed one-pot reaction using 2-bromobenzamides to obtain cis/cis-fused aza-tetracycles via an aza-Wacker–Heck protocol. As a synthetic application, the authors demonstrated the synthesis of the alkaloid γ-lycorane, which was obtained in good overall yield. The proposed mechanism begins with a Wacker-type reaction, where the Pd(II) catalyst coordinates to both the amide and the cyclic alkene and is followed by syn-aminopalladation. Next, the cyclic intermediate undergoes a β-hydride elimination, completing the aza-Wacker steps of the mechanism. Using control experiments, the authors highlighted the importance of DMSO as a ligand/solvent and O₂ to oxidize Pd(0) in the first reaction cycle. After completion of the aza-Wacker process, n-Bu₃P is added and generates in situ Pd(0), which triggers the subsequent Heck reaction steps. The previous cyclic intermediate and Pd(0) participate in an oxidative addition to the Ar–Br bond, followed by intramolecular syn-carbopalladation to furnish an all-cis ring system. Finally, a second β-elimination occurs, with subsequent product release from the catalytic cycle. In terms of sustainability and efficiency, it is worth mentioning the need for large amounts of catalyst and phosphine in the developed protocol (Scheme [15]).

An efficient enantioselective catalytic protocol for the synthesis of indole-fused bicyclo[3.2.1]octanes was proposed in 2021 by Ye and co-workers using a tandem aza-Wacker–Heck reaction under aerobic conditions, furnishing the products in good yields and enantioselectivities, although with inevitable protonolysis by-products (Scheme [16]).[32] The authors investigated the effect of commercial biphosphine chiral ligands, and (S)-Synphos afforded the best enantioselectivity. This important contribution to natural product synthesis employed diverse N-sulfonyl compounds, despite the use of Boc or acyl N-protecting groups being incompatible with the optimized conditions. While the electronic nature of the aniline portion proved to be relevant to the reaction performance, the steric effect played a small effect on the yield and selectivity. The proposed mechanism starts with Pd(II) coordination to the triple bond, followed by an aminopalladation reaction to furnish an indol-3-yl palladium intermediate, the formation of which was not from a competitive C–H activation mechanism, as proved by control experiments. The Heck reaction in the cycle starts with intramolecular double bond insertion followed by β-hydride elimination, which releases the product. Pd(II) is then regenerated by molecular oxygen and returns to the catalytic cycle (Scheme [16]).

Intermolecular Oxidative C–Nu Heterocoupling Reactions

The ease with which Pd(II) complexes facilitate the addition of nucleophiles to alkenes is a remarkable characteristic of such catalysts. Even though the use of palladium atoms in alkene functionalization reactions is widespread, an important issue is that the commonly formed alkyl palladium intermediates undergo competitive β-hydride elimination, thus leading to functionalization of only one carbon of the alkene.[33] A report by Bäckvall,[34] and later work of Lloyd-Jones and Booker-Milburn,[35] explored the difunctionalization of dienes that lead to electrophilic π-allyl intermediates, thus reducing the occurrence of β-elimination. On the other hand, C–H activation is also used in alkene difunctionalization chemistry via formal cycloaddition processes under mild conditions, therefore reducing reaction steps and the generation of waste.[36]

In 2017, Zhang and collaborators proposed a 1,2-diamination reaction using sulfonyl-protected aromatic diamines and conjugated 1,3-dienes, furnishing tetrahydroquinoxalines in moderate to high yields. Molecular O₂ was employed as the oxidant under two sets of optimized conditions, concomitantly with Cu(OAc)₂ (Scheme [17]).[37] While several internal 2-substituted dienes were employed in the reaction to afford the cyclization products in high yields, terminal substituted dienes caused a noticeable decrease in the reaction performance. Also, diverse N-toluenesulfonyl-protected o-phenylenediamines were employed with good performance, regardless of their electronic nature. The proposed mechanism starts with coordination of the aromatic diamine to Pd(II), culminating in a five-membered metala­cycle intermediate according to in situ ¹H NMR and HRMS studies. Next, the diene also coordinates to the metal center, triggering a syn-aminopalladation reaction and resulting in a π-allyl palladium intermediate, a second amino­palladation reaction of which leads to the heterocyclic product (Scheme [17]).

Based on the previous 1,2-diamination reaction, the same group extended their aminopalladation method to accomplish the 1,4-diamination of conjugated dienes and aromatic diamines (Scheme [18]).[38] This reaction features several 4-substituted and 4,5-disubstituted derivatives. The performance seems linked to the choice of diene, as 1,2-dimethylcyclohexane afforded good results, irrespective of the diamine used. Also, diverse 2,3-disubstituted dienes were employed, both cyclic and acyclic, with yields varying from 25–93%. The remarkable change in chemoselectivity compared to the previous report seems to be related to the KI additive. The proposed mechanism starts with the reaction between the palladium catalyst, potassium iodide, and the diamine, forming an intermediate in which the iodine is coordinated to palladium, whilst avoiding formation of the five-membered ring metalacycle intermediate responsible for the 1,2-diaminations explored earlier.[37] Thus, the Pd–I intermediate allows the aminopalladation reaction to occur at both ends of the 1,3-diene. Next, the diene coordinates to palladium, triggering an aminopalladation reaction and forming a π-allylpalladium intermediate. Finally, a second aminopalladation furnishes the 1,4-diamination product. The Pd(0) formed in this step is oxidized by molecular oxygen and returns to the catalytic cycle (Scheme [18]).

In a recent extension of the aforementioned 1,2- and 1,4-diaminations, Zhang and co-workers explored a Pd(II)-catalyzed cyclization between ortho-aminophenols and 1,3-dienes to obtain functionalized 1,4-benzoxazines (Scheme [19]).[39] Interestingly, the proposed method furnishes different products depending on the solvent utilized. For example, by using dimethyl sulfoxide, the 1,2-oxyamination product is preferred, whereas the use of acetonitrile favors 1,2-aminooxygenation. With these substrates the reactions proceed in high yields and selectivity in both solvents, regardless of the electronic nature of the substituents on the aminophenols. The mechanism of this transformation was studied by Zhang and Chen by way of experimental studies and DFT calculations.[40] The proposed mechanism involves two nucleopalladation steps. Control experiments showed that interconversion between the observed products was not operative, and it was found that the chemoselectivity of the reaction was determined during the nucleopalladation step, in which the solvent plays a pivotal role in the selectivity by acting as a ligand for the catalyst. The proposed reasoning for the different selectivity is related to attractive S=O^…H–C non-covalent interactions involving the SO₂-unity of the tosyl group. The acetonitrile guides the coordination of the diene cis to the N-toluenesulfonyl group and is stabilized by interactions involving the CH₂ groups of butadiene. However, a stronger attractive interaction between the methyl groups of DMSO and the N-toluenesulfonyl group causes coordination of the diene trans to the Ts group, thus inverting the selectivity (Scheme [19]).

In 2019, Gong and Han described an asymmetric Pd(II)-catalyzed intermolecular annulation between aromatic N-alkoxyaryl amides and substituted 1,3-dienes using a novel Pyrox derivative ligand, furnishing diverse heterocycles in high yields and enantioselectivities, thus allowing the synthesis of a range of chiral heterocycles from these simple starting materials (Scheme [20]).[41] The authors explored several 3-amide indole derivatives as substrates, obtaining good enantioselectivities and yields. The results showed that various substituents on the benzene ring were well tolerated. Also, amides from other heterocycles, such as benzofuran, benzothiophene, furan and thiophene, were well tolerated under the reaction conditions. As for the diene scope, diverse 1-aryl-1,3-butadienes could be utilized. The mechanism was studied by means of competitive KIE experiments, which revealed a significant isotope effect. This supported a first step involving C–H activation, which is directed by amide group, followed by alkene insertion forming a π-allyl intermediate. This intermediate is susceptible to intramolecular nucleophilic attack by the nitrogen to afford the product. The Pd(0) that is formed by reductive elimination in the last step is then oxidized by molecular oxygen and returns to the catalytic cycle (Scheme [20]).

Intramolecular Oxidative (C–C) Carbocyclization Reactions

Hetero-carbocycles are important building blocks present in biologically active natural products. These elegant motifs can be obtained by intramolecular dehydrogenative C–C bond construction, by direct connection of two C–H bonds[42] or of two neighboring C–H bonds in the same moiety, following Baldwin’s rules in the presence of Pd(II) and an oxidizing agent.[43] Beyond functional-group-based transformations, in which a C–H bond is converted into a pre-synthesized functional group to react with an organo-metallic/halide via traditional cross-coupling reactions,[44] the generation of C–C bonds selectively from two different C–H bonds leading to an overall formal loss of H₂ is a potential tool for direct transformations.[45]

In 2017, Lei and collaborators described an innovative palladium-catalyzed aerobic (1+2) annulation to generate strained cyclic scaffolds, such as 3-azabicyclo[3.1.0]hex-2-enes (Scheme [21]).[46] The reaction involves bond breaking via an α-C(sp³)–H palladation pathway, following olefin insertion and an inhibited β-H-elimination, allowing a second novel palladation at the same position. Furthermore, biaryl and heteroaromatics were tolerated. Kinetic studies were realized, indicating that oxygen diffusion and oxidation of Pd(0) were fast steps in this reaction, besides the involvement of the catalyst in the turnover-limiting step. These results also corroborated with the knowledge that a second C–H metalation and reductive elimination might be the slow steps of the catalytic cycle. The mechanism starts with generation of an enamine via tautomerization of an imine, which is followed by palladium insertion into the olefin to give a complex with a C–Pd bond. A second olefin insertion leads to a heterocycle dihydropyrrole intermediate via a 5-exo-trig cyclization, whilst a second intramolecular C–H palladation and reductive elimination provides the desired product. Finally, oxygen regenerates Pd(II) from Pd(0) (Scheme [21]).

In 2019, Han and Zhang developed a straightforward construction of [6.5.6]-tricyclic indole δ-lactams via a Pd-catalyzed aerobic oxidative Heck reaction (Scheme [22]).[47] The development of this methodology using indole derivatives appeared dependent on the basicity of pyridine ligands, suggesting that the nitrogen in these cores enhanced the catalytic activity of the metal catalysts. Evaluation of Pd complexes required the combination of two ligands, i.e., pyridine and phosphinamide ligands, in a molar ratio of 4:1. Thus, the use of a mixed ligand guaranteed a well-balanced basicity for effective coupling. A wide range of substrates was examined and the methodology successfully tolerated different substituents on the indole ring and on the terminal olefin. Functional groups on the side chain of indole presented broad compatibility with protected amino functionalities, esters, and hydroxy groups, potentially working as directing groups. Finally, construction of quaternary carbon centers, bridged cycles and related natural products expanded the applicability of the reaction. The redox cycle of the palladium catalyst for this 6-exo-trig annulation was proposed to proceed via Pd(I)/Pd(III) species based on experimental HRMS detection. Strong observed m/z peaks were related to palladium complexes assigned to Pd(III) species. Additionally, a KIE with k _H/k _D = 5.5:1 suggests that C–H activation should be the rate-determining step. These results supported a mechanism starting with oxidation of Pd(II) to a Pd(III) complex in the presence of oxygen. This complex, guided by the heteroatom in the side chain, forms a transition state with the substrate. Next, C–H bond activation takes place producing a σ-Pd-complex, which suffers migratory insertion, followed by β-hydride elimination to generate the desired product with exclusively non-conjugated double bonds. Finally, the Pd complex is regenerated in the presence of O₂ to give the active species of the catalytic cycle (Scheme [22]).

In the same year, Satyanarayana and Ramesh reported a palladium-catalyzed aerobic oxidative coupling of ortho-(alkynyl)styrenes and allylic alcohols via a 6-endo-dig annulation to obtain polysubstituted naphthalenes (Scheme [23]).[48] The optimum conditions for this intramolecular cycloaromatization involved the use of PdCl₂ in an open-air atmosphere. The plausible catalytic cycle begins with coordination of the Pd(II) species to the triple bond of the styrene substrate, with the resulting intermediate undergoing an intramolecular 6-endo-dig cyclization via formation of a carbocation intermediate and HX elimination to restore the aromaticity. Migratory insertion of the allylic alcohol followed by β-hydride elimination produces the product after tautomerization. Subsequently, Pd(II) is regenerated in the presence of O₂ (Scheme [23]).

In further studies based on the previously discussed syntheses of fused heteropolycyclic aromatic compounds, Sahoo and Pal recently developed a reaction to access benz­imidazo[1,2-a]quinoline-fused isoxazoles for the first time using a Pd(II)-catalyzed intramolecular dehydrogenative coupling under aerobic conditions in the presence of pivalic acid as an additive (Scheme [24]).[49] The scope of the reaction was explored with different electron-demand groups present on the isoxazole and benzimidazole moieties. A possible catalytic cycle starts with palladium coordination to the nitrogen atom of the benzimidazole, with migration to the C2-position in this same core via a metallotropism-triggered mechanism. Subsequently, intramolecular C–H bond cleavage takes place for a concerted metalation deprotonation. Based on KIE studies, C–H activation steps as the rate-limiting step were discarded. Finally, reductive elimination provides the product, whilst the active Pd(II) species is regenerated by oxygen (Scheme [24]).

Intermolecular Oxidative C–C Coupling Reactions

As previously mentioned, molecules can be obtained by cross-dehydrogenative coupling (CDC), not only via an intramolecular path, but also in an intermolecular fashion, allowing the direct construction of C–C bonds and generating H₂ as the only side product. Intermolecular direct C–H coupling reactions are also a powerful and useful synthetic tool as additional synthetic steps are not required to prepare he substrates. The process functions with two active sites, one on each component of the reaction.

Cyclization Reactions

In 2017, Wu and co-workers reported a direct approach for obtaining acridines (Scheme [25]).[50] This regioselective annulation of non-symmetrical cyclohexanones and 2-aminophenyl ketones comprises an intermolecular coupling, proceeding via an intermediate and subsequent intramolecular cyclization. The standard conditions using a Pd(II) catalyst in comparison to other metals was attractive due to its effective regeneration with molecular oxygen. Besides, the use of a 2-aminopyridine as a ligand was necessary for yield improvement, with citric acid as an additive at 110 °C in toluene (82% yield). An investigation of the scope showed good tolerance towards alkyl and aryl groups, as well as other cyclic ketones for diversification of the core structures. Based on control experiments, a possible reaction mechanism was described starting with a Friedländer annulation between the 2-aminophenyl ketone and the cyclohexanone in the presence of citric acid to afford 1,2,3,4-tetrahydroacridines, which undergo imine–enamine tautomerization to generate an enamine species. The enamine species then undergoes palladation and a sequential β-hydride elimination. Regeneration of active Pd(II) by O₂ restarts the catalytic cycle and releases the observed product (Scheme [25]).

Using a similar strategy, Ibrahim and Behbehani described a route to fused N-heterocycles and obtained novel, unparalleled diaza-dibenzo[a,e]azulenes and diaza-dibenzo[a]fluorenes (Scheme [26]).[51] This protocol involves a palladium-catalyzed carboxylic acid induced synthesis using a Q-tube, in which the reaction is safely conducted at high pressure under an oxygen atmosphere in a short reaction time. Investigation of the reaction parameters started with 1-amino-2-iminopyridine and benzosuberone substrates to access diaza-dibenzo[a,e]azulenes. The scope of this coupling reaction was also studied, showing good tolerance towards a diverse range of substrates. Additionally, other benzocyclic ketones such as tetralones, thiochromones and chromones were successfully applied. The proposed mechanism involves a traditional Pd(II)/Pd(0) redox process, starting with nucleophilic attack of the NH₂ moiety on the carbonyl of the benzocyclic ketone. This is followed by an acid-assisted dehydration to generate an imine intermediate. After tautomerization, imine palladation triggers an intramolecular electrophilic aromatic palladation assisted by an acetate ion, affording a palladacyclic intermediate. The product is released after a reductive elimination step and easily tautomerizes to provide the dibenzo[a,e]azulene. Pd(0) is reoxidized by molecular oxygen assisted by acetic acid to regenerate the Pd(II) species (Scheme [26]).

The use of epoxides as an alternative to alkylating reagents in coupling reactions was first reported by Wang and co-workers in 2021 (Scheme [27]).[52] This protocol manages to overcome the preference for formation of a Pd-alkoxide via ring opening of the epoxide, instead favoring attack of these species on the amide carbonyl group. This leads to a lactonization product rather than a β-hydrogen elimination pathway, which would afford a different product. For this purpose, the use of appropriate base-promoted β-hydride elimination affords the desired isoquinolones. This Pd-catalyzed cascade reaction of N-alkoxybenzamides with oxirane derivatives assisted by triethylamine under an air atmosphere tolerates a wide scope of N-methoxybenzamides and epoxides to afford the corresponding isoquinolone derivatives. Applications of this process either in late-stage modification (estrone) or in the total syntheses of rupreschstyril, siamine and cassiarin A have been described. The mechanism of this transformation begins with cyclometalation of the benzamide with Pd(II) followed by coordination with the epoxide. A ring-opening process then generates the Pd-alkoxide species. Next, β-hydride elimination affords the carbonyl product and nucleophilic addition of nitrogen on the carbonyl group followed by dehydration affords the isoquinolone products. Pd(0) is oxidized by air to Pd(II), which returns to the catalytic cycle (Scheme [27]).

Cross-Coupling Reactions

Escaping from traditional aryl coupling partner sources such as halides, boronic acids and diazonium salts, Chen and Liu provided a new approach for the application of sodium arylsulfinates (Scheme [28]).[53] Their transformation provides 2,5-diaryloxazole-4-carboxylates via a desulfitative arylation in the presence of a Pd-complex catalyst, an appropriate ligand and a base under an O₂ atmosphere. The scope exhibited high functional group tolerance with respect to the phenyl moieties. A possible mechanism has been described. First, C–H functionalization of the 2-aryl-4-carboxylate forms a palladium complex, with subsequent ligand exchange occurring between this intermediate and sodium benzenesulfinate. A desulfinative followed by reductive elimination affords the product and a Pd(0) species. Oxidation of Pd(0) by O₂ regenerates the active catalyst to complete the catalytic cycle (Scheme [28]).

Huang and co-workers reported a palladium-catalyzed C–H olefination of uracils and caffeines via an oxidative Heck reaction (Scheme [29]).[54] Their optimization studies evaluated the effect of mono-N-protected amino acids (MPAAs), with the best results seeming to accelerate the Pd(II)-catalyzed reaction with Z-Phe-OH. By employing the optimized conditions using the MPAA, pivalic acid as an additive and oxygen as the oxidant, the scope was explored with various acrylate and styrene olefin partners as well as with different N-protecting groups on the uracil and caffeine moieties. The reactions efficiently formed C5-alkenylated products and C8-alkenylated E-stereoselective products, respectively. The proposed mechanism starts with ligand exchange of Pd(OAc)₂ with Z-Phe-OH and PivOH to form the activated Pd(II) complex, which is followed by C–H insertion of Pd(II) to the uracil or the caffeine. Subsequent migratory insertion to the olefin and reductive elimination releases the product and forms Pd(0). Finally, regeneration of Pd(II) from Pd(0) by molecular oxygen completes the catalytic cycle (Scheme [29]).

In 2019, Musaev and Lewis reported an important study regarding the enantioselective C–H functionalization of N,N-dimethylaminomethylferrocene using N,N-dimethyl­acrylamides, in which a mono-N-protected amino acid (MPAA) plays a pivotal role in the formation of di-palladium complexes as active catalytic species, with the mechanism being rationalized using kinetic analysis, mass spectrometry and DFT calculations (Scheme [30]).[55] Using the continuous variation kinetic method, the authors demonstrated the formation of a bridged di-palladium core (Pd₂MPAA) in the reaction medium, which was confirmed by high-resolution mass spectrometry by observing the formation of MPAA-Pd ions. These dual palladated species were responsible for the stereoinduction in the reaction, in contrast with previous reports[56] in which a mono-palladated species was described as a key intermediate. In the proposed mechanism, N,N-dimethylaminomethylferrocene and acetate ligands coordinate with an off-cycle palladium species that exists in equilibrium with a competent precatalyst. Pd₂MPAA originates from this precatalyst, consisting of acetate-bridged ­dimer, by coordination of Boc-Phe and assembly of a pallada­cycle. Next, association with one N,N-dimethylacrylamide molecule followed by an insertion event results in C–C bond formation. Next, β-elimination takes place together with oxidation of the palladated species by molecular O₂. After product release, another substrate binds to the palladium core and a final C–H activation step is assumed as the selectivity-determining event, and characterized by C–Pd bond formation (Scheme [30]).

In 2020, Yu and Shi reported groundbreaking findings regarding the ligand-enabled remote Pd-catalyzed C–H activation of aliphatic carboxamides, where selectivity towards the γ-position could be favored in the presence of more accessible β-C–H bonds by using strained bicyclic alkenes as coupling partners (Scheme [31]).[57] In general, the new methodology presented broad scope with respect to the aliphatic carboxamides and strained norbornadiene derivatives, providing several examples of products obtained in moderate to excellent yields. DFT calculations and deuterium-labeling experiments suggest a switch in site-selectivity by favoring reversible steps to achieve a Pd migration process, thus enabling γ-alkylation. In the proposed mechanism, Pd(dba)₂ is first oxidized by air to form Pd(II), which coordinates with two 2-pyridone-type ligands. After deprotonation, the aliphatic carboxamide coordinates with the palladium, and this is followed by a β- or γ-C–H activation event, both via a concerted metalation–deprotonation mechanism. After a second ligand displacement and Pd insertion, the Pd-migration event turns out to be favorable only for the γ-pathway, with subsequent protonation and ligand exchange affording the desired product (Scheme [31]).

Xu and collaborators reported a site-selective C–H bond (hetero)arylation of thiazole derivatives in 2019 by employing N-heterocyclic carbene palladium complexes under aerobic conditions (Scheme [32]).[58] This novel protocol showed high efficiency towards the formation of C–C bonds between thiazole scaffolds and brominated arenes/hetero­cycles. A low catalyst loading was utilized and the process exhibited broad scope and high yields, even when strongly deactivated and highly congested bromides were employed. The authors synthesized a series of bulky Pd-NHC-type complexes, proving that such steric hindrance had a direct effect on the catalytic efficiency (Scheme [32]).

In 2019, Matsumoto and co-workers reported the first example of an oxidative aniline–aniline cross-coupling reaction catalyzed by the heterogenous palladium catalyst Pd/Al₂O₃ and using oxygen as the terminal oxidant. Anilines with pyrrolidine groups could be oxidized under mild conditions, with the process being considered an economical and environmentally friendly method for the synthesis of nonsymmetrical biphenyls (Scheme [33]).[59] In the proposed mechanism, the iminium ion undergoes a single-electron transfer with the Pd catalyst, resulting in the formation of a radical cation intermediate that preferentially couples with the less sterically hindered position of the aniline moiety to afford the desired product after tautomerization. Subsequently, molecular oxygen oxidizes the reduced catalyst to regenerate the active palladium species (Scheme [33]).

A straightforward method for the preparation of β‑aryl‑C‑glycosides was reported by Kandasamy and co-workers in 2019 via oxidative Heck coupling of sugar-derived enones and aryl boronic acids, presenting high yields and stereoselectivity towards the C1 carbon (Scheme [34]).[60] The reaction presented broad substrate scope and good protecting group tolerance, in which a variety of enones derived from d-glucal, d-galactal, l-rhamnal, d-rhamnal, and l-arabinal could be functionalized, with the functional groups remaining intact at the end of the process. A plausible mechanism starts with coordination of 1,10-phenanthroline with palladium acetate, followed by transmetalation with the corresponding aryl boronic moiety. The resulting complex coordinates with the α-face of the enone, providing a palladated intermediate that exists in equilibrium with a Pd-enolate species via a palladotropic shift. Lastly, syn-β-H elimination, and reductive elimination forms the LPd(0) species. This complex reacts with molecular oxygen to form the desired C1 aryl enone and an oxygenated complex (LPdO₂), which is converted into Pd(OAc)₂L in the presence of AcOH. The authors detected the formation of a hydrolyzed 1,4-addition product under acidic conditions that could be generated via the Pd-enolate intermediate (Scheme [34]).

Recently, Stahl and co-workers reported a Pd-catalyzed oxidative arylation of indoles using O₂ as the oxidant, during which the catalyst plays a pivotal role in the regioselectivity (Scheme [35]).[61] This straightforward methodology provided access to both C2- and C3-arylated indoles in good yields with >10:1 selectivity under ligand-free conditions, and a switch in selectivity was enabled by the use of a 2,2′-bipyrimidine as an ancillary ligand in addition to the previous catalyst system. Supported by DFT calculations, the authors showed that the switch in the selectivity arises from a change in the mechanism, whereas the absence of a ligand promotes an oxidative Heck pathway, the use of a ligand leads to a C–H activation/reductive elimination event (Scheme [35]).

Homo-Coupling Reactions

In 2021, De Vos and co-workers reported a straightforward reaction regarding the C–C coupling of two indoles via palladium-catalyzed C–H/C–H cross-coupling driven by molecular oxygen, in which the regioselectivity was tuned by controlling the electronic properties of the aromatic carboxylate ligands (Scheme [36]).[62] The C–H/C–H coupling between indoles presented moderate scope and moderate to high yields, with some substrates requiring more drastic conditions for coupling to occur. Based on KIE experiments and DFT calculations, the authors proposed a concerted metalation-deprotonation (CMD) at the C2 position, due to the more labile character of the C–H bond at this site. Next, a ligand-substitution reaction is proposed to be the rate-determining step, with the indole acting as a nucleophile and AcOH as the leaving group. The formed C2 carbocation, stabilized by N1, justifies the electrophilic attack of Pd(II) at the C3 position. This scenario led the authors to investigate the amount and the electronic character of the used ligand. By changing the molecular oxygen pressure during reactions, the authors were able to modulate the C2 and C3 selectivity of the indoles, offering a complete explanation based on kinetic experiments and computational investigations. A quantitative Hammett study showed that more basic benzoate ligands favored initial C–H activation at the C2 position, whereas less basic ligands turned the selectivity towards the more electron-rich C3 position (Scheme [36]).

In 2016, Zhou and Wang reported a highly efficient catalytic system composed of Pd(OAc)₂/TfOH and O₂ as the sole oxidant to promote the conversion of benzene into biphenyl (Scheme [37]).[63] This new catalytic manifold operates with a small amount of Pd(OAc)₂ (0.073 mol%) and provided a high turnover number for the Pd species (180). Excellent selectivity (98%) was observed, no co-catalyst was required and the reaction took place in a mixture of acetic acid/water as the solvent. The authors provided a full study based on DFT calculations and UV/Vis absorption spectroscopy, showing the importance of the use of a strong acid such as TfOH in the formation of reaction intermediates like the Wheland complex and the subsequent aryl-Pd intermediates. In the proposed mechanism, Pd(OAc)₂ reacts with TfOH to generate an active Pd(O₃SCF₃)₂ species that undergoes electrophilic aromatic substitution with benzene to form an o-arylpalladium(II) intermediate. Next, interaction of the Pd(II) intermediate with another benzene molecule generates a diarylated Pd(II) intermediate, which undergoes reductive elimination to afford the biphenyl product. Catalyst regeneration occurs via interaction of the Pd(II) species with O₂ to form a palladacycle species, with subsequent reduction and formation of H₂O by reaction with TfOH (Scheme [37]).

A two-step process to produce 4,4′-dimethylbiphenyl (DMBP) was recently reported by Lobo and co-workers, in which the authors used 2-methylfuran as a readily available feedstock obtained from the depolymerization of hemicellulose to xylose via furfural formation (Scheme [38]).[64] In the new procedure, 2-methylfuran was submitted to Pd-catalyzed oxidative coupling in the presence of trifluoroacetic acid (TFA) and a high pressure of molecular oxygen to afford the intermediate 5,5′-dimethyl-2,2′-bifuran (DMBF). This was subsequently converted into DMPB via catalysis with phosphoric acid supported on silica in a tandem Diels–­Alder and dehydration fashion. Two possible mechanisms were described regarding the limiting step (monometallic or bimetallic), in which monometallic exhibits a first-order dependence on Pd as C–H activation is the limiting step, while the bimetallic pathway shows a first-order or second-order dependence on Pd, depending on which step is rate-limiting. In general terms, it starts with Pd(II)-mediated activation of two Ar–H bonds, and is followed by reductive elimination and reoxidation of the Pd(0) species by molecular oxygen (Scheme [38]).

In 2020, Sohtome and Sodeoka reported a formal aerobic oxidative cross-coupling of benzofuranones with subsequent functionalization with azo compounds promoted by Pd-μ-hydroxo complexes in a radical–radical coupling fashion (Scheme [39]).[65] Using a persistent transient radical strategy, the dimerization of benzofuranones was achieved in high yields by using a highly bulky palladium-based dimer as a co-catalyst and molecular oxygen (1 atm). The dimeric species were used as intermediates in the synthesis of azo compounds in a single-flask operation, providing nitrogenated benzofuranones in moderate to high yields (Scheme [39]).

Stahl and co-workers reported in 2020 the possibility of using auxiliary reagents in a non-stoichiometric amount to achieve an oxidative C–H/C–H coupling of thiophenes under an oxygen atmosphere. These ligands and co-catalysts improved the reaction yield when combined with catalytic amounts of Pd(OAc)₂, 1,10-phenanthroline (phd), Cu(OAc)₂ and benzoquinone (BQ) (Scheme [40]).[66] Satisfactory results were obtained with a large variety of substituents, but the authors did not explore electron-donating groups. Also, the thiazole reaction did not give a satisfactory yield. Insights were made about the role of Cu(OAc)₂, with this salt not being a redox facilitator of Pd(OAc)₂ activity, as shown in previous work.[67] The Cu co-catalyst acts as a C–C coupling promotor, with little influence on the C–H activation step. The authors postulated the contribution of the co-catalyst as a Lewis acid in phd-bridged bimetallic species, bringing kinetic advantages over other conventional bimetallic interactions (Scheme [40]).

Aerobic Dehydrogenative Coupling/­Functionalization

Extensive progress in direct C–H palladation cross-coupling by metal insertion has been well-documented over the years.[68] The development of this area has overcome two main challenges: (1) sufficient reactivity for the cleavage of strong C–H bonds, and (2) the control of site-selectivity.[69] To improve these aspects, functional groups next to the ­C–H bond can assist metalation by controlling the selective site through coordination of the heteroatom to the metal center.[70] Besides, dehydrogenative coupling, which is commonly used to bring about aromatization, has also been used in the strategy of direct C–H palladation, activating chemically inactive positions through formation of double bonds that are susceptible towards subsequent functionalization.

In 2017, Huang and co-workers presented an external-ligand-free conversion of N- and C-containing cyclic compounds into their respective aromatic rings using Pd catalysis (Scheme [41]).[71] Several inorganic bases were tested, with ^t BuOK being the only one competent of participating in the proton abstraction step involving the N–H bond. All the tested Pd catalysts were able to promote oxidation of tetrahydroquinolines to quinolones. An investigation of the scope showed that substrates with electron-donating and electron-withdrawing groups attached to the N-heterocycle were all oxidized in excellent yields, and even substituted pyrroles and benzofurans were obtained by utilizing the present conditions. The proposed mechanism starts with Pd(II) complexation to the deprotonated nitrogen followed by a β-hydride elimination. Next, the HPdX species undergoes reductive elimination under basic conditions to give Pd(0), which is readily oxidized with O₂ and performs another β-hydride elimination to afford the desired product (Scheme [41]).

Focusing on high efficiency and atom economy, Wu and Jiang developed conditions using a Pd(II) catalyst, TsOH, water, DMSO and molecular oxygen as a terminal oxidant to prepare a wide range of quinoline products in moderate to excellent yields from different allyl benzenes and anilines (Scheme [42]).[72] The reaction mechanism proceeds via coordination of the allylic bond to the Pd(II) species, which allows attack of water to form an enol, which is rapidly oxidized by molecular oxygen. After imine formation between cinnamaldehyde and the aniline, a conjugate addition takes place during which another molecule of the aniline, mediated by acid, reacts with the imine converting it into a labile diazetidinium cation. Finally, the desired product is obtained due to the occurrence of irreversible cyclization/elimination steps. The inactive Pd species can be regenerated after oxidation by O₂ and restarts the catalytic cycle (Scheme [42]).

Kim and collaborators developed an efficient one-pot synthesis of flavanones using tandem Pd(II) catalysis, which allowed chemically unactivated β-sites of chromanones to react through a dehydrogenation step, followed by conjugate addition with arylboronic acids (Scheme [43]).[73] Reaction scope studies showed that a wide spectrum of substrates with electron-donating and electron-withdrawing groups, alkyl moieties and halogen atoms could be used to prepare the respective flavanones, showing the wide range of applicability of this methodology. To achieve the maximum yield, the role of the acid medium was investigated, leading to lower conversion into the respective chromones by a dehydrogenation step in which the arylboronic acid is converted into its corresponding arene, whereas acidic conditions were necessary to improve the yield of the conjugate addition step. The proposed mechanism involves coordination of Pd(II) at the α-site of the chromanone, leading to a β-hydride elimination event with formation of the chromone product possessing an activated β-site. This intermediate undergoes conjugate addition with an aryl-Pd(II) intermediate, originating from the arylboronic acid via a transmetalation step. The desired product is obtained after a protonolysis step. The Pd(0) formed in the dehydrogenation step is oxidized by O₂ to give the active Pd(II) species and restart the cyclic process (Scheme [43]).

Inspired by previous work, Park and Kim recently developed an oxidative aza-intramolecular cyclization of N-Tf-2′-aminodihydrochalcones to prepare aza-flavanones under milder conditions and in short reaction times by using ligand-free Pd(II) catalysis (Scheme [44]).[74] The scope of this methodology was investigated in detail and yields of up to 84% were obtained. The mechanism proceeds via complexation of Pd(II) at the α-site of the carbonyl compound, leading to β-hydride elimination and the formation of the chalcone product with an activated β-site that undergoes an aza-Michael addition. The Pd(II) species proved crucial to the dehydrogenation process, but the aza-Michael addition does not require the presence of a metal species when the substrate possesses α,β-unsaturation (Scheme [44]).

Oxidative C–H Functionalization

Functionalization of organic molecules through activation of C–H bonds is one of the most attractive strategies in chemical synthesis due to the advantages in terms of step-, atom- and redox-economy when compared to functionalization reactions involving two other complementary functional groups forming a new bond.[75] Many methodologies have been developed in this area involving different strategies, especially the ones employing transition-metal complexes as catalytic species.[76] All these strategies share the challenge of driving C–H activation in a selective manner and preserving other reactive functional groups present in the structure.[77]

In 2020, Singh and co-workers reported a metalaphotoredox reaction involving oxygenation of the C–H bonds of aromatic rings under visible-light irradiation to construct C(sp²)–O and C(sp³)–O bonds, occurring through oxidation of the Pd(II) species to high-valent Pd(III) or Pd(IV) intermediates mediated by a photocatalyst and O₂ (Scheme [45]).[78] Electron-donating and electron-withdrawing groups on the oxime moiety were explored, giving satisfactory results for monoacetoxylation, except for ortho-substituted substrates due to steric hindrance. A second acetoxylation reaction was observed only in trace quantities for the same steric effect. The methodology was investigated with aromatic scaffolds to obtain hydroxylated products in good yields for most substrates, except for ortho-substituted examples due to steric reasons and for which moderate yields were observed. The mechanism starts with C–H activation of the free substrate by complexation with a Pd(II) center, which is oxidized to Pd(IV) by the superoxide species generated in situ by the photocatalyst in combination with light, and then transformed back into Pd(II) via reductive elimination and C–O bond formation. Kinetic isotope effect experiments showed that C–H bond cleavage would be the rate-determining step of the mechanism (Scheme [45]).

In 2017, Yu and co-workers achieved the first enantio­selective borylation of C(sp³)–H bonds via Pd(II) catalysis by employing chiral acetyl-protected aminomethyloxazolines (APAO) as ligands and bis(pinacolato)diboron. Excellent ee values were obtained and O₂ was employed as the sole oxidant (Scheme [46]).[79] To achieve enantioselectivity, the authors reported the importance of two chiral centers being present in the oxazoline moiety, with the asymmetric induction occurring through steric repulsion between its two bulky groups and the cyclobutane ring. The scope was explored with different cyclic amides ranging from cyclopropanes to cyclohexanes; even substrates with coordinating atoms and with α-tertiary and α-quaternary carbon centers were successfully borylated (Scheme [46]).

Recently, the Dash group reported a site-selective monoacylation of carbazole derivatives via a straightforward methodology using easily accessible materials. They employed N-hydroxyphthalimide (NHPI) as a radical initiator, toluene, oxygen as the sole oxidant, and Pd(II) catalysis (Scheme [47]).[80] The authors explored the scope with a variety of toluene- and mono- and disubstituted N-pyridyl­carbazole derivatives, obtaining regioselective acylated products without using any additional solvent. The reaction takes place by the formation of phthalimido-N-oxyl (PINO) from NHPI and O₂, followed by abstraction of a hydrogen from the toluene to form a benzylic radical that is rapidly oxidized by molecular oxygen leading to formation of a benzoyl radical. The substrate forms a complex with the Pd(II) species, which leads to C–H activation by abstraction of a carbazole proton. Thus, the Pd(II) intermediate reacts with the benzoyl radical via oxidative addition, oxidizing the Pd(II) to Pd(IV), whilst the Pd(II) species is regenerated after reductive elimination of the acylated product (Scheme [47]).

Summary

In summary, this short review has surveyed Pd(II)-catalyzed oxidative couplings and functionalizations of cyclic compounds using molecular oxygen as the sole oxidant. Significant advances in this field have been noted in the literature in recent years, with the use of appropriate ligands or solvent-based ligands to enhance the stability of Pd(0). A broad spectrum of reaction partners has been analyzed, and it is noteworthy that Pd is particularly versatile under oxidative conditions, allowing its use in very different catalytic processes, using activated or non-activated substrates under mild reaction conditions, and tolerating diverse functional groups and densely functionalized starting materials. Undoubtedly, much work still needs to be done, especially in the development of enantioselective catalytic systems, since few examples are found in the literature. Additionally, studies involving scale-up and applications in technological processes are still rare, and this is certainly an important area taking into consideration the enormous industrial potential, as exemplified by the Wacker reaction. But perhaps the least investigated characteristic is related to the nature of the catalytic species under aerobic conditions. In this sense, mechanistic investigations are an attractive goal, for example, by seeking to identify catalytic species and off-­cycle intermediates. This type of knowledge would certainly be very useful for the optimum design of catalytic systems, aiming at better stability and reactivity, and considering that most of the conditions described herein use a very large catalytic load.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Authors

Publication History

Received: 15 September 2021

Accepted after revision: 19 November 2021

Accepted Manuscript online:
19 November 2021

Article published online:
25 January 2022

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart

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