Efficient Aerobic Oxidation of Organic Molecules by Multistep Electron Transfer

Abstract This Minireview presents recent important homogenous aerobic oxidative reactions which are assisted by electron transfer mediators (ETMs). Compared with direct oxidation by molecular oxygen (O2), the use of a coupled catalyst system with ETMs leads to a lower overall energy barrier via stepwise electron transfer. This cooperative catalytic process significantly facilitates the transport of electrons from the reduced form of the substrate‐selective redox catalyst (SSRCred) to O2, thereby increasing the efficiency of the aerobic oxidation. In this Minireview, we have summarized the advances accomplished in recent years in transition‐metal‐catalyzed as well as metal‐free aerobic oxidations of organic molecules in the presence of ETMs. In addition, the recent progress of photochemical and electrochemical oxidative functionalization using ETMs and O2 as the terminal oxidant is also highlighted. Furthermore, the mechanisms of these transformations are showcased.


Introduction
Thed evelopment of economic and environmentally benign synthetic methods has recently become an important but challenging goal in organic chemistry. [1] Oxidation reactions are involved in ab road range of chemical transformations that allow the facile preparation of various useful commodity chemicals and building blocks. [2] However,i n most cases stoichiometric oxidants such as iodosylbenzene, hypochlorite,p ersulfate,a nd metal salts (Cu II ,A g I ,C r VI , Mn VII )a re used, which leads to low atom economy,a nd considerable amounts of undesired waste.A mong various oxidants,m olecular oxygen (O 2 )a nd hydrogen peroxide (H 2 O 2 )a re environmentally friendly and highly atom-efficient oxidants that generate no toxic byproducts. [3] Compared to H 2 O 2 ,O 2 is much less expensive since air can often be used, but it has the disadvantage that rigorous precautions are required for large-scale applications,e specially for high pressure reactions.
Over the past decades,h omogenous catalytic aerobic oxidations have provided the basis for the streamlined conversion of various feedstocks into valuable products in industry. [4] However,t he direct reoxidation of the reduced form of the substrate-selective redox catalyst (SSRC red )byO 2 is always challenging due to the often high energy barrier of this reaction step,a sw ell as its low efficiency and selectivity (Scheme 1a). [5] This "oxidation problem" can be explained by the slow electron transfer between SSRC red and O 2 ,c ompared to the fast deactivation of the catalyst.
One elegant strategy is to mimic biological oxidation systems and insert electron transfer mediators (ETMs) between the substrate-selective redox catalyst and O 2 (Scheme 1b). [6] It is widely recognized that naturese legant way of overcoming the "oxidation problem" is through the orchestration of av ariety of enzymes and co-enzymes that act as catalysts and ETMs, which lower the overall barrier for electron transfer from SSRC red to O 2 . [7] These ETMs are ap art of what is called the electron transport chain (ETC), where O 2 is typically used as the terminal oxidant. This chain bypasses the high kinetic barrier associated with the direct oxidation of SSRC red by O 2 and leads to alower overall energy barrier via stepwise electron transfer.
One of the first examples of the use of an ETM in an aerobic oxidation was the Wacker process.C upric chloride was used as an ETM to facilitate electron transfer between Pd 0 and O 2 . [8] An ature-inspired aerobic oxidative reaction using two ETMs was reported by the Bäckvall group in the late 1980s. [9] Later on, several groups explored this concept by developing mild and efficient coupled catalyst systems with ETMs in various oxidative functionalizations. [10] In general, ag ood candidate ETM in ar edox reaction should have the appropriate redox potential, lead to al ow energy barrier in the electron transfer, be stable enough under the reaction conditions,a nd be compatible with the redox processes involved. In 2008, we summarized catalytic oxidations with O 2 and H 2 O 2 as terminal oxidants in multistep electron This Minireview presents recent important homogenous aerobic oxidative reactions whichare assisted by electron transfer mediators (ETMs). Compared with direct oxidation by molecular oxygen (O 2 ), the use of acoupled catalyst system with ETMs leads to alower overall energy barrier via stepwise electron transfer.This cooperative catalytic process significantly facilitates the transport of electrons from the reduced form of the substrate-selective redox catalyst (SSRC red )t oO 2 , therebyi ncreasing the efficiency of the aerobic oxidation. In this Minireview,wehave summarized the advances accomplished in recent years in transition-metal-catalyzed as well as metal-free aerobic oxidations of organic molecules in the presence of ETMs.Inaddition, the recent progress of photochemical and electrochemical oxidative functionalization using ETMs and O 2 as the terminal oxidant is also highlighted. Furthermore,t he mechanisms of these transformations are showcased. Scheme 1. Aerobic oxidation of organic molecules with electron transfer mediators. transfer processes, [11] and arelated review was also published by Chang in 2004. [12] After the publication of these reviews, considerable advances have been made in this field.
Herein we provide an overview of the recent advances in aerobic oxidations assisted by ETMs.I nt his Minireview,w e have selected recent representative examples of aerobic oxidation of organic molecules with redox catalysts,w hich are divided into three sections (Scheme 2): 1) transitionmetal-catalyzed aerobic oxidations,u sing metal catalysts based on palladium, ruthenium, and iron;2)organocatalyzed aerobic oxidations,u sing organocatalysts such as guanidine, NHC,D DQ,a nd nitroxyl;a nd 3) recent progress in photoand electrocatalyzed oxidative functionalizations.Itshould be noted that there are also systems where the catalyst is oxidized directly by O 2 . [13] However,t his strategy always requires higher reaction temperature,a ncillary ligands,o r external additives to facilitate the direct oxidation. Coupled catalytic systems with ETMs constitute an important complement to homogenous oxidation chemistry,w hich has greatly expanded the use of O 2 as ag reen oxidant. We hope this Minireview will be of value to chemists involved in oxidation reactions in both academic and industrial research and that it will stimulate further development in green and sustainable chemistry.

Metal-Catalyzed Aerobic Oxidation with ETMs
Palladium-catalyzed aerobic oxidations have emerged as powerful and valuable tools in modern organic synthesis. Despite significant advances in this field, as evere problem often encountered is the fast aggregation of palladium black from participating palladium species (Pd-H or Pd 0 )w hich slows down and finally stops the homogenous reaction (Scheme 3). Extensive endeavors to solve this problem have focused on the use of air-stable ligands such as sulfoxides, amines,p yridines,a nd carbenes,t op revent Pd 0 precipitation during the catalytic cycle.S tahl and co-workers published ar eview on the use of various ligands that improve catalyst efficiency and stability in aerobic oxidations with increased selectivity. [14] On the other hand, coupled catalytic systems with an ETM can facilitate the relay of electrons between the Pd catalyst and O 2 .These coupled catalytic systems have been demonstrated to be highly efficient in Wacker oxidations, allylic oxidations,C-H activations,a nd carbocyclizations. TheP d-catalyzed Wacker-Tsuji reaction is one of the most famous homogenous reactions which provides reliable access to carbonyl compounds (aldehydes or ketones) under mild reaction conditions. [15] This reaction refers generally to the transformation of aterminal or 1,2-disubstituted olefin to an aldehyde or ketone,r espectively,t hrough the action of Pd II ,w ater, and ac o-oxidant. Conversion of ethylene to acetaldehyde by stoichiometric PdCl 2 was discovered over ac entury ago; [16] however,i tw as not until sixty years later that ac atalytic method was developed. In the 1950s, researchers at Wacker Chemie reported that atransformation took place in an aqueous,a cidic solution of catalytic PdCl 2 and astoichiometric amount of CuCl 2 through which oxygen was bubbled. [17] Later on, in the 1960s Farbwerke Hoechst developed ao ne-stage process using oxygen as the terminal oxidizing agent (Scheme 4). [18] This process quickly attracted great interest around the world since acetaldehyde is an important intermediate in industrial chemistry,with over two million tons being produced annually today.
To encourage sufficient mixing of the organic reactants with the aqueous phase,aco-solvent is generally employed along with water. When dimethylformamide (DMF) is used as ac o-solvent with CuCl 2 as the ETM under atmospheric pressure of oxygen, the reaction is called the "Tsuji-Wacker oxidation". [19] This version allows arange of olefins,which are not soluble in water, to be used. Them echanism of the Wacker oxidation has been studied for over 60 years with one of the earliest studies being reported by Smidt et al. [15c,20] The generally accepted mechanism is the one in which an alkene coordinates to Pd II with subsequent nucleophilic attack by water and b-hydride elimination to afford the carbonyl product. Conventionally,C uCl 2 and O 2 are used as the oxidants to regenerate Pd II from the Pd 0 formed.
Despite the success of the Wacker reaction, the presence of chloride ions has anegative effect on the reaction efficiency and causes selectivity problems through the formation of chlorinated side products.T osolve these problems associated with the use of chloride,B äckvall reported ac hloride-free Wacker oxidation by using Pd(OAc) 2 together with hydroquinone (HQ) and ametal macrocycle,such as acobalt Schiff base complex (Co(salophen)) and iron phthalocyanine (FePc) as ETMs (Scheme 5). [21] This triple catalytic system has led to af aster and more efficient reaction, giving high yields under mild conditions with 5mol %P dc atalyst as shown in Scheme 6a.T his catalytic procedure is approximately 16 times faster than the corresponding chloride-based Wackertype oxidation. [22] However,Bäckvallsreaction was limited to the oxidation of terminal olefins.T his is because internal olefins show relatively low reactivity and selectivity.K aneda and coworkers developed ac opper-free Wacker oxidation of internal olefins. [23] This protocol requires the use of relative high oxygen pressures (3-9 atm) in an autoclave.I n2 013, Grubbs developed ag eneral and practical Pd-catalyzed oxidation to access ketones from aw ide variety of internal olefins (Scheme 6b). [24] Theu se of HBF 4 as an acid additive in the DMA/MeCN/H 2 Os olvent mixture resulted in high conversion of internal olefin 5 to the corresponding ketone 6.I ti s likely that ad icationic complex is generated in situ in the presence of HBF 4 through protonation of the acetate ligands. This process showed wide functional-group tolerance for the preparation of ketones with atriple catalytic system using O 2 as the terminal oxidant.
Another key issue in the Wacker oxidation is the regioselectivity of the product. [25] Them ajority of terminal alkenes produce predominately methyl ketones,w hich is in accordance with Markovnikovsr ule.F eringa reported that anti-Markovnikov selectivity could be achieved through the Pd-catalyzed oxidation of ester-o ra mide-protected allylic substrates using BQ as an oxidant. [26] Theregioselectivity can be explained by the weak coordinating influence of the Lewis basic oxygen or nitrogen functional groups.I n2 013, Grubbs developed anitrite-modified Wacker-type catalyst system for the conversion of simple aliphatic alkenes 7 to aldehydes 8 (Scheme 6c). [27] Thea ddition of an itrite source,s uch as AgNO 2 ,l ed to good anti-Markovnikov selectivity and synthetically useful yields.I ti sp roposed that the catalyst facilitates in situ formation of an NO 2 radical from the nitrite salt, followed by aradical-type addition of the NO 2 radical to the olefin at the terminal position. This determines the ultimate origin of anti-Markovnikov selectivity.
Palladium-catalyzed allylic C-H activation represents ap owerful synthetic strategy in organic chemistry. [28] In 1990, the Bäckvall group reported ac oupled quinone/metal macrocycle system for the aerobic allylic acetoxylation of olefins. [21b] This reaction is efficient and gives the allylic acetate in good yield through the oxidation of cyclohexene under atmospheric O 2 .However,only acetic acid was applied as the coupling partner in this reaction. In 2010, Stambuli showed that the sulfide ligand L1 can improve the allylic acetoxylation of terminal olefins 9 when O 2 is used in combination with 5mol %C u(OAc) 2 (Scheme 7a). [29] Also, in this reaction only acetic acid was applied as the coupling partner.Amethod compatible with diverse carboxylic acids was developed by the Stahl group (Scheme 7b). [30] Theuse of 4,5-diazafluoren-9-one (DAF, L2)asaligand, in combination with aq uinone/FePc co-catalyst system leads to efficient oxidation of Pd 0 by O 2 which then promotes acyloxylation of the allylic CÀHb ond. Am ore sterically hindered 2,6dimethylbenzoquinone (Me 2 BQ) was found to improve the product yield. Theq uinone is not only ac o-catalyst for transporting electrons between the Pd catalyst and the metal macrocycle,but can also act as aligand, which coordinates to the Pd species during the catalysis. [31] In addition to C-O couplings,P d-catalyzed allylic C-H amination was reported by the White group in 2016 (Scheme 7c). [32] Theuse of redoxactive co-catalysts,C o(salophen), and HQ as ETMs significantly improved the reaction efficiencyu nder atmospheric O 2 .
An example of aerobic C(sp 3 )ÀHactivation was reported by the Sanford group in 2012, which focused on the use of NaNO 3 or NaNO 2 as an ETM in aP d-catalyzed aerobic oxidation of unactivated C(sp 3 ) À Hbonds using oxime ethers 11 or quinoline derivatives 12 as effective directing groups (Scheme 8). [33] This process proceeds through the decomposition of nitrate to NO 2 which is the active ETM. Thepresence of NO was confirmed through the addition of butylated hydroxytoluene (BHT) to the reaction, which is known to form 2,6-di-tert-butyl-4-methyl-4-nitrosocyclohexa-2,5-dienone (TBMND) on exposure to NO.
Theo xidative functionalization of simple aromatic C À H bonds was originally reported by Fujiwara and Moritani. [34] Much progress has been achieved in this field following this pioneering work, which is now recognized as ap owerful method for the construction of valuable building blocks. [35] TheS tahl group described the use of nitrite and nitrate sources (fuming HNO 3 )asNO x -based redox mediators in the acetoxylation of benzene (Scheme 9a). [36] These reaction conditions avoid the formation of biphenyl as aside product, and strongly favor formation of phenyl acetate 13 over nitrobenzene (selectivity PhOAc:PhNO 2 up to 40:1). Under the optimized reaction conditions,with 0.1 mol %Pd(OAc) 2 , 136 turnovers of the Pd catalyst are achieved with only 1atm of O 2 pressure.T he Bäckvall group reported an efficient Pdcatalyzed aerobic oxidative dehydrogenative coupling between arene 14 and nonbiased olefin 15 (Scheme 9b). [37] This reaction took place in the presence of catalytic amounts of BQ and FePc as the ETMs under ambient oxygen pressure.

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In 2017, Jiang and Li described aP d-catalyzed cascade oxidative arylation/olefination for the synthesis of dihydrobenzofurans 17 (Scheme 10). [38] Similar to Wacker-type oxidations,t he use of ac atalytic amount of Cu(OAc) 2 as the ETM allows efficient reoxidation of the Pd catalyst under aerobic conditions.I nt his reaction, the addition of BQ increased the yield from 76 %t o85 %. This result can be explained by the fact that BQ stabilizes the Pd 0 species through the in situ generation of Pd 0 -BQ complexes,a nd no palladium black was observed. Themechanism of the reaction involves electrophilic metalation of substrate 16 by PdX 2 (X = OTFA or OAc) to give aryl-Pd species Int-1. Then, intramolecular insertion of the olefin forms the alkyl-Pd intermediate Int-2,w hich is followed by insertion of activated olefin to give Int-3. A b-hydride elimination affords the corresponding product 17 and the active Pd II species is regenerated through oxidation of Pd 0 by CuX 2 /O 2 .
Pd-catalyzed oxidative carbocyclizations have become powerful methods for the construction of carbocyclic and heterocyclic compounds. [39] TheB äckvall group reported an aerobic catalyst system for the oxidative carbocyclization of allenyne 18 to five-membered carbocycle 19 (Scheme 11). [40] Initially,the coordination of the allene and alkyne units to the Pd II center leads to an allenic C(sp 3 )-H bond cleavage and the generation of avinylpalladium intermediate Int-4. Carbocyclization of Int-4 via alkyne insertion gives Int-5 and reaction with the free alkyne generates Int-6. Reductive elimination from Int-6 provides the target product 19 and aP d 0 species. Interestingly,t here was no competition between the two terminal alkynes,a nd the five-membered carbocycle was obtained in high selectivity.W ith the assistance of BQ and Co(salophen) as ETMs,aerobic oxidation of Pd 0 regenerates Pd II .D ifferent substituted allenynes were subjected to the reaction conditions and gave the corresponding five-membered carbocycles in good yields and high stereoselectivity.
This catalyst was also applied for as elective olefinassisted Pd-catalyzed oxidative carbocyclization of enallene 20 via remote olefin insertion to afford substituted cyclohexenes 21 and 22 (Scheme 12). [41] Ther eaction of Pd II with enallene 20 bearing the assisting olefin produces vinylpalladium Int-8 via allenic CÀHbond cleavage,which is promoted by the coordination of the allene and the assisting olefin to Pd II in Int-7. Then, the vinylpalladium intermediate Int-9 would be generated from Int-8 via ligand exchange (from

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Chemie proximal olefin to remote olefin). Next, Int-9 would undergo ar emote olefin insertion to give cyclic intermediate Int- 10. Subsequent transmetalation of Int-10 with B 2 pin 2 or arylboronic acid, followed by reductive elimination would give the target cyclohexene derivatives 21 or 22.T he biomimetic approach using catalytic amounts of Co(salophen) and BQ as the ETMs led to aerobic borylative and arylative carbocyclizations in good yields.
In addition to the previous catalyst system with the quinone and metal macrocycle as separate ETMs,ahomogenous hybrid catalyst was developed by Bäckvall, in which the metal macrocycle and quinone are merged into one molecule (Scheme 13 a). [42,43] In 1993, Bäckvall developed an efficient hybrid catalyst (Co(TQP), Co-1), involving ac obalt-porphyrin with pendant hydroquinone groups in one molecule for aerobic Pd-catalyzed 1,4-diacetoxylation of 1,3-cyclohexadiene,b ut the stereoselectivity of the reaction was moderate and the catalyst was difficult to synthesize.In2008, the same group designed an improved hybrid Schiff base-hydroquinone as aredox relay catalyst for aerobic oxidations. [43] In this type of hybrid catalyst, cobalt Schiff base complexes were chosen as the oxygen-activating center because of their demonstrated efficiencyi nc oupled aerobic oxidation, and their simple and modular synthesis.F or example,t he hybrid cobalt catalyst Co-2 Co(salmdpt)-HQ (salmdptH 2 = bis-[3(salicylideneimino)propyl]methylamine), and Co-3 Co-(salophen)-HQ were used as efficient ETMs in the Pdcatalyzed aerobic oxidative carbocyclizations of enallene 23 and 24 (Scheme 13 b). [44] Thea uthors mentioned that the slower reaction of 24 to 25 with Co-3 is most likely due to the fact that Co-3 is quite insoluble in ethanol.
TheC o(salophen)-HQ Co-3 was also found to be highly efficient in the Pd-catalyzed aerobic carbocyclization of the rationally designed enallenyne 26 (Scheme 14 a). [45] The enallenyne 26 contains three different CÀC p-bond functionalities (allene,o lefin, and alkyne groups), and this combination presents ac hallenge concerning the control of regioselectivity in the reaction. Interestingly,c yclization takes place between the allene moiety and the distal triple bond of the enallenyne 26,w hile the olefin group remains intact. The mechanism is similar to that of the carbocyclization of enallene 20,i nw hich a" helping olefin" triggers the C(sp 3 ) À Hb ond cleavage followed by ar eplacement of the coordinated pendant olefin by the remote unsaturated C-C ligand. Control experiments showed that the initial step of the allenic C(sp 3 )-H bond cleavage by Pd II requires the coordination of ap endant olefin bond in the substrate.T he use of Co-3 resulted in as ignificantly higher reaction rate than that with Co(salophen) and quinone as separate ETMs.T he authors proposed that the hybrid catalyst, Co-3 enhances the overall electron transfer between the Pd catalyst and O 2 ,d ue to intramolecular electron transfer in Co-3,t hereby leading to amore efficient overall reaction under aerobic conditions.In addition, the catalyst Co-3 is also highly efficient in the oxidative carbocyclization of dienallenes 28 and bisallenes 29 to six-or seven-membered heterocycles 30 and 31 (Scheme 14 b). [46] Scheme 13. a) Design of abifunctional hybrid ETM for aerobic oxidations;b)Applicationsint he Pd-catalyzed carbocyclization of enallenes. Ruthenium-catalyzed oxidation reactions are ac lass of important transformations in organic synthesis. [47] In the past decades,mild dehydrogenations of alcohols to give aldehydes or ketones through the use of low-valent Ru complexes have been reported, which were subsequently extended to the dehydrogenation of amines to imines. [48] TheS tahl group reported aR u-based catalyst system that shows high activity for amine oxidation, including the successful aerobic dehydrogenation of diverse tetrahydroquinolines at room temperature with ambient air (Scheme 15). [49] In this work, the ruthenium complex [Ru(phd) 3 ] 2+ (Ru-1,p hd = 1,10-phenanthroline-5,6-dione) was applied for the oxidative dehydrogenation of tetrahydroquinoline 32 to afford quinoline 33.T he structure of [Ru(phd) 3 ](ClO 4 ) 2 was characterized via X-ray crystallography.The use of aCo(salophen) as the ETM allows the reaction to proceed efficiently.I nt he absence of Co-(salophen), the reaction is very slow.T he synthetic utility of the catalytic method was demonstrated by the preparation of various medicinally relevant quinolines.
Ad imeric ruthenium catalyst called Shvo catalyst Ru-2 has been known since the 1980s and has been demonstrated to be highly efficient in al arge variety of hydrogenation and oxidation transformations. [50] Thed issociation of Ru-2 gives two complementary active monomeric species Ru-3 and Ru-4 bearing anon-innocent active functionalized ligand (Scheme 16 a). Thehydroxycyclopentadienyl ligand in Ru-3 has aproton on the oxygen and the Ru center has ahydride ligand. The proton and the hydride are involved in hydrogen transfer reactions.T he cyclopentadienone in Ru-4 has ap rotonacceptor site at oxygen and ahydride-acceptor site at the Ru center and can catalyze oxidations.T he dehydrogenation of alcohols occurs through an outer-sphere pathway in which the alcohol binds to the Ru complex through bridging hydrogens (Int-11). [51] Thea lcohol complex Int-11 undergoes simultaneous hydride and proton transfer to produce Int-12,w hich finally releases the ketone.T he Bäckvall group developed efficient Ru-catalyzed aerobic oxidations via ab iomimetic catalytic system (Scheme 16 b). [52] Dehydrogenation of the alcohol by Ru-4 affords the oxidized product and the ruthenium hydride Ru-3.T he latter species is reoxidized by O 2 with the aid of an electron transfer system. TheS hvo catalyst (Ru-2)showed excellent activity and amore electronrich quinone,2,6-dimethoxy-1,4-benzoquinone (DMBQ), and Co(salmdpt) complex Co-4 were used as the ETMs.T he authors speculated that the slow step in the electron transfer chain is the reoxidation of the hydroquinone,a nd the more electron-rich 2,6-dimethoxy-1,4-hydroquinone is oxidized faster than the 1,4-hydroquinone by [Co(salmdpt)] ox .T he oxidation of alcohols,amines,diols,and amino alcohols could be performed with high selectivity to give the corresponding carbonyl products in generally good yields.
Given the cost-effective and sustainable nature of earthabundant first-row transition metals,the development of less toxic, inexpensive 3d metal catalysts for aerobic oxidations has gained considerable momentum as am ore environmentally friendly and economically attractive alternative. [53] Iron is the most abundant transition metal in the Earthscrust. In addition to the economic benefit, the development of ironcatalyzed reactions also provides an opportunity to access complementary chemoselectivity and discover new reactivity. [54] Cyclopentadienone iron hydride complexes such as Fe-1 (Scheme 17 a) have been known since the 1950s,long before the Shvo precatalyst. In the 1990s,K nçlker and co-workers isolated the first iron hydride hydroxycyclopentadienyl complex Fe-3 from the precursor Fe-2 and confirmed its structure

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Minireviews by X-ray crystallography. [55] Thef irst catalytic application of hydrogenations and transfer hydrogenations with this type of catalyst was reported by Casey and Guan in 2007. [56] Since then, given their unique catalytic behavior,e asy access from abundant iron sources,a nd good stability,t here has been ad ramatic increase in the number of catalytic applications using these catalysts. [57] An outer-sphere mechanism of dehydrogenation analogous to that of the Shvo system was proposed for iron-catalyzed oxidations. [58] Very recently, Bäckvall reported on an iron-catalyzed aerobic biomimetic oxidation of alcohols (Scheme 17 b). [59] Thee lectron transfer from the alcohol to O 2 occurs with the aid of three coupled catalytic redox systems,l eading to al ow-energy pathway.I n this reaction, the (cyclopentadienone)iron tricarbonyl complex Fe-4 was utilized as the substrate-selective dehydrogenation catalyst along with DMBQ and an oxygen-activating Co(salmdpt) complex as ETMs.V arious primary and secondary alcohols were oxidized in air to their corresponding aldehydes and ketones in good to excellent yields with this method.
The N-heterocyclic carbene (NHC)-catalyzed aerobic oxidative esterification of aldehydes with alcohols is ag reen and sustainable process for the synthesis of versatile esters. SundØna nd co-workers described as trategy for oxidative NHC-catalyzed esterifications of a,b-unsaturated aldehydes 40 in the presence of FePc and 2,6-di-tert-butylphenol (2,6-DTBP) as ETMs (Scheme 19). [61] In this reaction, the key steps are the oxidation of homoenolate intermediate Int-14 by quinone (from 2,6-DTBP) to the acyl azolium Int-15, which reacts with the alcohol to give the unsaturated ester 41 and regenerating NHC Int-13. Ther eaction has ab road substrate scope and the products were isolated in good to excellent yields.T he use of air as the terminal oxidant offers an environmentally friendly and inexpensive way to scale up this important oxidation reaction via NHC chemistry.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is apowerful oxidant, which has been applied in many oxidative reactions. [62] Catalytic oxidation systems with DDQ as the catalyst and O 2 as the terminal oxidant have seen much development in recent years.Huand Shen reported the use of DDQ as substrate-selective redox catalyst for the aerobic oxidative deprotection of PMB (p-methoxybenzyl) ether, alcohol oxidation, and aromatization of indoline in high conversions and excellent selectivity (Scheme 20). In this reaction, FePc was employed as the ETM, and O 2 was used as the environmentally benign terminal oxidant. [63] Fort he purpose of reusing the FePc employed as ETM, it was supported in multiwalled carbon nanotubes (MWCNTs), which provided good reactivity and recyclability in the aerobic deprotection of PMB ethers.
Nitroxyl catalysts,s uch as TEMPO (2,2,6,6-tetramethylpiperidine N-oxyl) and ABNO (9-azabicyclo[3.3.1]nonane Noxyl), have been identified as highly effective catalyst systems for aerobic oxidation (Scheme 21). [64] Va rious oxidation products can be obtained with the metal/nitroxyl catalyst system under aerobic conditions.F or example,M aa nd coworkers reported an Fe(NO 3 ) 3 ·9 H 2 O/TEMPO catalyst system for the selective and mild aerobic oxidation of aw ide range of alcohols to carboxylic acids. [65] TheS tahl group demonstrated highly practical applications of the Cu/ABNOcatalyzed aerobic oxidative coupling of alcohols and amines for the synthesis of diverse amides. [66] Homogenous aerobic oxidation with nitroxyl catalysts has also been achieved with other transition-metal salts (e.g. Mn, Co,a nd Ce) as cocatalysts. [67] Among these metals,t he Cu/nitroxyl catalyst systems,u sing nitroxyls such as TEMPO and ABNO,h ave emerged as some of the most efficient catalysts available for aerobic oxidations.T he mechanism and kinetics of Cu/ nitroxyl catalysis has been extensively studied by Brackman, Semmelhack, Sheldon, Koskinen, and Stahl in the past years. [68] Thes implified catalytic mechanism with the Cu/ TEMPO system is depicted in Scheme 21. Initially,a erobic oxidation of Cu I and TEMPOH affords the Cu II -OH species Int-17 and TEMPO.T he oxidation of the alcohol proceeds through the formation of the Cu II -alkoxide species Int-18, which is then followed by hydrogen atom transfer to TEMPO with formation of the aldehyde and TEMPOH. TheC u/ TEMPO catalyst system was extensively studied and applied in the aerobic oxidation of alcohols and amines.A ne legant review on this topic was published by Stahl and co-workers in 2014. [69] N-hydroxyphthalimide (NHPI) is also widely used as as ubstrate-selective redox catalyst (SSRC) in selective oxidation reactions.S everal 3d transition metals,s uch as V 4+ ,Fe 3+ ,Co 2+ ,and Cu 2+ have been utilized as ETM catalysts together with NHPI as SSRC for the oxygenation of C(sp 3 ) À Hb onds (Scheme 22 a). [70] Ther eaction initially converts NHPI to the phthalimide N-oxyl radical (PINO) in the presence of the 3d metal catalyst and O 2 .PINO then mediates the selective Habstraction from the benzylic CÀHbond in 42 to generate an organic radical Int-19 that can react with O 2 . Then H-atom transfer generates peroxide intermediate Int-21 and finally produces the oxygenated products 43,s uch as ketones or aldehydes and water. Several reviews were published recently on this topic, where the scope and mechanism of these reactions are discussed. [71] Stahl demonstrated an aerobic oxidation of heteroarenes 44 to their corresponding heteroarylketones 45 using NHPI and Co-  [72] Theheterocycles 44 play an important role in this type of oxidation since an enamine or as imilar tautomer can often form which is more amenable to oxidation at the benzylic position. In 2018, Va n Humbeck reported an interesting related dual-catalysis approach in which Fe(BF 4 ) 2 ·6 H 2 O, ab orate ligand, and aNO 2 -substituted analogue of NHPI were used in tandem for the aerobic oxidation of substrates bearing an azaheterocycle (46 and 47)(Scheme 22 c). [73] Theiron complex is introduced to selectively oxidize ab enzylic position adjacent to an azaheterocycle because it can act as aL ewis acid, which coordinates to the nitrogen and weakens the CÀHbond at the benzylic position, making the hydrogen abstraction and subsequent oxidation easier.
Hypervalent iodine reagents are auseful class of chemical oxidants which find application in diverse chemical syntheses. [74] Thec urrent liabilities of hypervalent iodine reagents include the frequent need for stoichiometric amounts of these compounds and their wasteful synthesis using metal-based oxidants such as KMnO 4 ,N aIO 4 ,o xone,a nd mCPBA. Very recently,the Powers group reported an efficient formation of hypervalent iodine compounds from aryl iodides,c obalt, aldehydes,a nd O 2 (Scheme 23). [75] In this reaction, CoCl 2 ·6 H 2 Oa cts as an initiator for aldehyde autoxidation. Thea erobically generated peracid Int-22 (e.g.A cOOH) allows for the oxidation of the aryl iodide to the hypervalent iodine reagent Int-23 (e.g.P hI(OAc) 2 ). With this method, af amily of hypervalent iodine reagents were successfully generated in situ using O 2 as the terminal oxidant. The hypervalent reagents were used in aerobic oxidation in av ariety of reactions,s uch as alcohol oxidation (50 to 51), a-oxygenation of acetophenone (52 to 53), bromination of a b-keto ester (54 to 55), and intermolecular C-H amination (56 to 57).

Metal-Free Aerobic Oxidations with ETMs
In the aerobic oxidation of organic molecules,many of the processes rely on am etal catalyst or co-catalyst to facilitate the redox process.However,the presence of trace amounts of metals in the desired products always has several negative effects for biological and medicinal applications.I nt his context, aerobic oxidations using metal-free catalytic systems are of great interest in organic synthesis. [76] Hu and Mo reported aD DQ/TBN (TBN = tert-butyl nitrite) catalyst system for the selective oxidation of benzylic alcohol 58 to the corresponding aldehyde 59 (Scheme 24). [77] Key to the success for this aerobic oxidation is that the NO released from TBN can act as an ETM between DDQ and molecular oxygen. Thes ame catalyst system can also be applied in the catalytic benzylic oxidation of the lignin b-O-4 model 60 to 61 in high yields for efficient biomass conversion and oxygenation of C(sp 3 )ÀHbonds. [78] Recently,Lei and coworkers described an oxidative C(sp 3 )-H/N-H cross coupling by introducing DDQ and TBN under aerobic conditions. [79] This amination reaction can be applied to aw ide range of alkyl (hetero)arenes 64 and triazoles,p yrazoles and their derivatives 65.T his reaction starts with ah ydrogen atom transfer (HAT) process between DDQ and the alkyl (hetero)arene 64,w hich then generates the alkyl radical Int-25. Subsequently as ingle-electron oxidation of the alkyl radical Int-25 leads to the alkyl cation Int-27,which reacts with the N-nucleophile 65 to furnish the amination product 66.Meanwhile,D DQH 2 is oxidized to DDQ by NO 2 ,w hich is generated from TBN and O 2 .
TEMPO is aw ell-known, commercially available,a nd stable nitroxyl radical. One-electron oxidation of TEMPO affords the oxoammonium species Int-28 which can be used

Angewandte
Chemie as an oxidant. Forexample,oxoammonium-mediatedalcohol oxidation results in two-electron reduction of the oxoammonium species to afford ah ydroxylamine Int-29. Hu and coworkers reported atransition-metal-free aerobic oxidation of benzylic and heteroaromatic alcohols,w ith TEMPO as an efficient substrate-selective redox catalyst (Scheme 25). [80] In this example,B r 2 and NaNO 2 are used as the co-catalysts to relay the electrons between TEMPOH and O 2 .Awide range of primary and secondary alcohols were effectively oxidized. In addition, the use of HBr/TBN or DDQ/TBN instead of Br 2 / NaNO 2 as ETMs also promotes the aerobic oxidation of alcohols to the corresponding carbonyl compounds in excellent yields.
It is worth mentioning that flavins,afamily of the most versatile redox cofactors in nature,c an be used as the substrate-selective redox catalyst for mild chemical oxida-tions. [81] Theg eneral catalytic cycle is outlined in Scheme 26. Theo xidation of the reduced flavin FlEtH Int-30 with O 2 occurs readily to give hydroperoxide FlEtOOH Int-31. Then, this intermediate oxidizes the substrate to the product, generating hydroxyl flavin FIEtOH Int-32. After elimination of the OH group to give FlEt + Int-33,areduction process occurs to regenerate FlEtH Int-30,a nd subsequently Int-30 can be oxidized by O 2 to Int-31.
In nature,flavins occurring in monooxygenases use O 2 as the oxidant. This process requires acofactor that reduces the hydroxyflavin that is produced after the hydroperoxyflavin has oxidized the substrate,a nd in nature this cofactor is NADPH (Scheme 26). In an elegant study,I mada, Murahashi, and co-workers mimicked this process with the development of af lavin-catalyzed aerobic oxidation of sulfides and tertiary amines at ambient temperature. [82] Hydrazine was used as astoichiometric reductant and constitutes amimic of the NADPH cofactor. In addition, other reductants such as metallic zinc, [83] Hantzsch ester, [84] and formic acid [85] were also applied in flavin-catalyzed aerobic oxidation.
Then aturally based flavin derivatives in Scheme 26 involving FlEtOOH (Int-31)h ave been used as SSRCs in aerobic oxidations,b ut not so far as ETMs.H owever,w ith ar elated flavin, involving the (N,N)-1,3-dimethyl isomer instead of the FlEtOOH (N,N)-3,10-dimethyl flavin, ahydrogen peroxide-based biomimetic asymmetric dihydroxylation of olefins was developed, where the flavin and N-methylmorpholine (NMM) act as ETMs with OsO 4 as the SSRC. [86] Carbery and co-workers demonstrated ac ationic flavinbased catalyst system in the biomimetic oxidation of benzylamines to imines (Scheme 27). [87] Thec ombination of as ynthetic flavin with alloxan significantly facilitates biomimetic amine oxidation to imines.T he mechanism of this aerobic oxidation combines several multistep electron transfer processes.Initially,the flavin catalyst Cat-2 is reduced by Me 2 Sto generate the neutral semiquinone Int-34. Subsequently,Hatom transfer (HAT) takes place between Int-34 and benzylamine 67 to give semiquinone Int-35 and a-amino radical Int-36. This a-amino radical Int-36 can reduce alloxan to ahydroxyl carbon radical Int-38 forming Int-37.

Photo-and Electrochemically Mediated Aerobic Oxidations with ETMs
Photoredox chemistry and electrochemistry have attracted broad interest for the development of green chemical synthesis.T hese transformations,w hich employ inexpensive, ubiquitous light and electricity constitute apowerful strategy for the activation of small molecules. [88] Photoredox catalysis offers access to the unique chemical reactivities of organic molecules in the excited state,which allows the generation of reactive intermediates with high redox potential in atransient state.E lectrochemistry also offers as olution to this issue by using electric current as the traceless redox agent, and the introduction of amediated electron transfer can occur against ap otential gradient, meaning that lower potentials are needed, reducing the probability of undesired side reactions. [89] In this section, we discuss recent examples in photoand electrochemically mediated aerobic oxidation reactions (Scheme 28).
Phenol is an important precursor for many chemicals and industrial products.O ne-step oxygenation of benzene to phenol is one of the dream chemical reactions. [90] The Fukuzumi group reported the direct oxygenation of benzene (69)t op henol (70)u nder visible-light irradiation of DDQ under aerobic conditions (Scheme 29 a). [91] This catalyst was also applied in the aerobic amination of aromatics and heteroaromatics by Lei and Koenig (Scheme 29 b). [92] This photooxygenation reaction is initiated by photoinduced electron transfer from benzene (69)t ot he triplet excited state of DDQ Int-41 to give abenzene radical cation Int-42 and aD DQ radical anion Int-43,t he protonation of which gives Int-45. Theb enzene radical cation Int-42 then reacts with nucleophiles such as water or amines to yield Int-44. Int-45 subsequently reacts with the Int-44 to form phenol or an aniline derivative,and DDHQ.TBN was used as an ETM to convert DDHQ to DDQ under aerobic conditions.The same catalyst system was also applied for the oxygenation of C(sp 3 ) À Hb onds in diarylmethane 72 to the corresponding ketones 73 (Scheme 29 c). [93] TheN icewicz group reported an efficient photoredoxbased catalyst system consisting of the photocatalyst Mes-Acr + BF 4 Cat-3,(Mes,mesityl;Acr, acridinium) and TEMPO for site-selective amination of avariety of simple and complex aromatics (Scheme 30). [94] Thea uthors proposed that an arene cation radical Int-46 is generated upon photoinduced electron transfer from the arene to an excited-state photoredox catalyst (Mes-Acr +* ). This arene cation radical Int-46 could react with imidazole,f ollowed by deprotonation to provide the radical intermediate Int

Angewandte
Chemie onates TEMPOH via ah ydrogen atom transfer process, ultimately forming H 2 O 2 and regenerating TEMPO. Samec and Wang developed an interesting photoinduced dearomatization of nonphenolic biaryl compounds to generate spirolactones (Scheme 31). [95] Thedearomatization can be performed via aerobic photocatalysis using Mes-Acr + BF 4 as the photocatalyst and TEMPO as the ETM. This reaction is induced by electrophilic attack of the carboxyl radical Int-48 generated from single-electron transfer with the excited photocatalyst Mes-Acr +* and substrate 76.C arboxyl radical Int-48 then induces dearomatization by intramolecular cyclization to form aspirodiene radical Int-49,which is then captured by O 2 to form Int-50 in aerobic systems,after which H-atom transfer generates peroxide intermediate Int-51 and finally spirodienone 77 is produced through the release of water. This method represents an ovel route to synthesize spirolactones from the biaryl motif.
Jiang and co-workers demonstrated ab enzylic oxygenation using an ovel photocatalyst, ad icyanopyrazine (DPZ) derivative in combination with catalytic amounts of N-hydroxysuccinimide (NHS) (Scheme 32). [96] In the presence of light, the photocatalyst DPZ is activated to an excited state DPZ*, which can oxidize NHS in as ingle-electron-transfer process.The succinimide-N-oxyl (SNO) radical then abstracts the Hatom at the benzylic C-H position of the substrate 78 or 79 to generate ab enzylic radical that reacts with O 2 ,f inally delivering the ketone 80 or 81.
Flavins have been extensively studied as organic photoredox catalysts for oxidative organic transformations. [97] For example,r iboflavin tetraacetate (RFT) is ar eadily available compound with an oxidation potential of + 1.67 V( vs.S CE) upon irradiation (l max = 440 nm). This characteristic allows RFT and its derivatives to function as photocatalysts in aerobic oxidations and the mechanism is depicted in Scheme 33 a. Upon irradiation, electron transfer followed by proton transfer between excited RFT* and urea results in thiyl radical Int-52 and semiquinone form (RFTC)-H. The thiyl radical Int-52 abstracts the a-hydrogen atom from the alcohol to produce a-hydroxyl carbon radical Int-53,w hich can further react with (RFTC)-H by hydrogen-atom transfer to afford the desired product ketone.Finally,the reduced species (RFT)-H 2 is oxidized by O 2 to regenerate the RFT catalyst and H 2 O 2 .Based on the interaction of RFT and urea, Koenig designed an efficient bifunctional catalyst consisting of aflavin backbone and athiourea group (Scheme 33 b). [98] This catalyst is able to catalyze the aerobic oxidation of 4-methoxybenzyl alcohol (82)tothe corresponding aldehyde 83 in low catalyst loading (TON = 580).
Thef ormation of H 2 O 2 as ab y-product is am ajor drawback of the RFT-catalyzed photocycle because H 2 O 2 can degrade RFT under irradiation which leads to the corresponding ketones being produced in poor yields.W olf reported that the addition of an iron complex can significantly improve the yield under aerobic conditions because the iron complex can catalyze H 2 O 2 disproportionation (Scheme 33 c). Thec ombination of the RFT and the biomimetic non-heme iron complex Fe(TPA)(MeCN) 2 ](ClO 4 ) 2 Cat-5 (TPA = tris(2pyridylmethyl)amine), gave the best yield of 85 from 84 under visible-light irradiation and aerobic conditions. [99] Many catalytic aerobic reactions operate with two halfreactions:1 )oxidation of an organic molecule,a nd 2) reduc-

Angewandte
Chemie tion of O 2 to water.E fficient reduction of O 2 to water is ac entral challenge in many aerobic oxidation reactions as well as in energy conversions. [100] Theelectrochemical oxygen reduction reaction (ORR) can be achieved by using electrontransfer mediators to promote efficiencya nd selectivity. Recently,t he Stahl group demonstrated that by combining nitroxyls (such as TEMPO) with NO x ,itispossible to achieve efficient electrocatalytic O 2 reduction at high potentials (Scheme 34). [101] In the coupled redox reactions,the nitrogen oxide catalyst drives aerobic oxidation of anitroxyl mediator to an oxoammonium species,w hich is then reduced back to the nitroxyl at the cathode.T he same group also explored amolecular cobalt complex, Co(salophen), and HQ as ETMs for the electrochemical reduction of O 2 to water. [102] They showed that redox cooperativity between Co(salophen) and HQ enables O 2 reduction at higher potentials and with faster rates than those observed with either individual catalyst partner.T hese coupled catalyst systems with ETMs demonstrate aunique strategy to achieve improved performance in electrochemical ORR.
It is widely recognized that simple aliphatic CÀHb onds are more difficult to oxidize and selectivity is more difficult to achieve compared with activated C(sp 3 )ÀHb onds (benzylic or allylic). [103] Recently,the Baran group reported an efficient aerobic electrochemical oxidation of unactivated C À Hbonds (in 86 and 87)t ot he corresponding ketones or alcohols (88 and 89)(Scheme 35 a). [104] Inspired by their previous work on the anodic allylic C-H oxidation, [105] in this reaction, the use of one equivalent of quinuclidine as an electrochemical medi-ator allows efficient electrooxidation of C À Hb onds.M echanistically,the electrochemical C-H oxidation involves aquinuclidine radical cation Int-54 generated through anodic oxidation. This high-energy species can homolytically cleave an unactivated CÀHb ond. Then ar eaction between the carbon-centered radical and O 2 affords the oxidation product. This method has the potential to facilitate the synthesis of complex molecules in good yields with high selectivity.Jensen presented ac ontinuous electrolysis system engineered for

Angewandte
Chemie NHPI-mediated electrochemical aerobic oxidation of benzylic C À Hb onds (Scheme 35 b). [106] Here,N HPI and pyridine were used as efficient mediators for electron transfer.T he deprotonation of NHPI by pyridine,f ollowed by anodic electron transfer, leads to aPINO radical. ThePINO radical subsequently mediates abstraction of ab enzylic hydrogen atom in 90 to generate abenzylic radical. This radical can be trapped by O 2 to form aperoxy radical, which then yields the carbonyl products 91.T he corresponding cathode reaction is the reduction of pyridinium cation to evolve H 2 and regenerate pyridine.T he use of an electrochemical flow system for aerobic oxidation enables ap rocess for further scaling-up and opens up potential for an industrial process.

Conclusion and Outlook
Aerobic oxidation reactions are of fundamental importance in chemical science and are widely applied in synthetic organic chemistry.Inthis Minireview,recent progress made in aerobic oxidations using electron transfer mediators has been summarized and discussed. Thec oupled catalytic system significantly facilitates the transport of electrons from the reduced substrate-selective catalyst to O 2 ,thereby increasing the efficiencyofaerobic oxidation. This strategy has proven to be powerful and valuable in the assembly of carbon-carbon and carbon-heteroatom bonds,w hich provides useful applications in homogenous catalysis and organic synthesis.
Despite the advances reported in recent years,wefeel that many exciting opportunities and challenges still lie ahead in the field of aerobic oxidative transformations: 1) Thed esign of novel and efficient ETMs is highly important and desirable for aerobic oxidations.F or example,t he use of chiral ETMs for stereoselective synthesis can be explored and that deserves more attention. Additionally,n ew concepts like solid-supported mediators can be developed in order to improve the efficiency of aerobic processes and simplify product isolation. Computational methods can also be routinely used to assist in tailoring the properties of redox catalysts to meet specific purposes. 2) Theuse of first-row transition metals as substrate-selective redox catalysts (SSRCs) is one of the key developments in aerobic oxidations,d ue to the abundance,l ow price,a nd low toxicity of these metals. 3) Ther ecent progress in photo-and electrochemical reactions in aerobic oxidations will attract broad interest for the development of green chemical synthesis.T hese transformations,which use inexpensive,ubiquitous visible light and electric current constitute apowerful strategy for the activation of small molecules.
Clearly,the field of mediated electron transfer in aerobic oxidation constitutes af ertile arena in which to conduct research. We have no doubt that many important and exciting developments will be forthcoming in the future.
As mentioned in the introduction, large-scale industrial applications with molecular oxygen at high pressure require rigorous precautions.T he advantage of many of the biomim-etic aerobic oxidations described in this Minireview is that they can often be run under mild conditions at ambient pressure.Furthermore,dilute concentrations of O 2 as in air or < 5% O 2 in N 2 can also be used in many cases.U nder the latter conditions the safety problems are dramatically reduced.

Addendum
After the submission of the present article,t wo papers related to its content on aerobic oxidation have been published by Stahl and co-workers. [107] Thef irst paper [107a] describes the Pd-catalyzed aerobic homocoupling of thiophenes using phenanthroline dione and aC u(OAc) 2 as electron transfer mediators (ETMs). In the second article [107b] involving Pd-catalyzed aerobic C-H arylation it was found that tailored quinones such as 2,5-di-tert-butyl-p-benzoquinone led to high turnovers (> 1900) on Pd.