CâC Bond Activation with Molecular Oxygen

Article pubs.acs.org/accounts

Oxygenation via C−H/C−C Bond Activation with Molecular Oxygen Yu-Feng Liang† and Ning Jiao*,†,‡ †

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing 100191, China ‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China CONSPECTUS: The selective oxidation of organic molecules is a fundamentally important component of modern synthetic chemistry. In the past decades, direct oxidative C−H and C−C bond functionalization has proved to be one of the most efficient and straightforward methods to synthesize complex products from simple and readily available starting materials. Among these oxidative processes, the use of molecular oxygen as a green and sustainable oxidant has attracted considerable attention because of its highly atom-economical, abundant, and environmentally friendly characteristics. The development of new protocols using molecular oxygen as an ideal oxidant is highly desirable in oxidation chemistry. More importantly, the oxygenation reaction of simple molecules using molecular oxygen as the oxygen source offers one of the most ideal processes for the construction of O-containing compounds. Aerobic oxidation and oxygenation by enzymes, such as monooxygenase, tyrosinase, and dopamine β-monooxygenase, have been observed in some biological C−H bond hydroxylation processes. Encouraged by these biological transformations, transitionmetal- or organocatalyst-catalyzed oxygenation through dioxygen activation has attracted academic and industrial prospects. In this Account, we describe some advances from our group in oxygenation via C−H/C−C bond activation with molecular oxygen as the oxidant and oxygen source for the synthesis of O-containing compounds. Under an atmosphere of O2 (1 atm) or air (1 atm), we have successfully incorporated one or two O atoms from O2 into simple and readily available substrates through C−H, C−C, CC, and CC bond cleavage by transition-metal catalysis, organocatalysis, and photocatalysis. Moreover, we have devised cyclization reactions with molecular oxygen to construct O-heterocycles. Most of these transformations can tolerate a broad range of functional groups. Furthermore, on the basis of isotope labeling experiments, electron paramagnetic resonance spectral analysis, and other mechanistic studies, we have demonstrated that a single electron transfer process via a carbon radical, peroxide radical, or hydroxyl radical is involved in these aerobic oxidation and oxygenation reactions. These protocols provide new approaches for the green synthesis of various α-keto amides, α-keto esters, esters, ketones, aldehydes, formamides, 2-oxoacetamidines, 2-(1H)-pyridones, phenols, tertiary α-hydroxy carbonyls, p-quinols, β-azido alcohols, benzyl alcohols, tryptophols, and oxazoles, which have potential applications in the preparation of natural products, bioactive compounds, and functional materials. In most cases, inexpensive and low-toxicity Cu, Fe, Mn, or NHPI was found to be an efficient catalyst for the transformation. The high efficiency, low cost, high oxygen atom economy, broad substrate scope, and practical operation make the developed oxygenation system very attractive and practical. Moreover, the design of new types of molecular-oxygen- or air-based oxidation and oxygenation reactions can be anticipated.

1. INTRODUCTION Oxidative reactions are of critical importance in nature and are fundamental transformations in chemical synthesis.1 The development of selective, practical, sustainable, and environmentally friendly oxidation reactions is one of biggest challenges facing synthetic organic chemists in both academia and industry. An essential consideration in developing more economically and environmentally sustainable oxidation technologies is the selection of the stoichiometric oxidant, where versatility, expense, and environmental impact need to be addressed.2 Molecular oxygen has been regarded as an ideal oxidant because of its natural, inexpensive, and environmentally benign characteristics and therefore offers attractive academic and industrial prospects.3 Oxygen-containing compounds are attractive synthetic targets on account of their wide presence in a great number © 2017 American Chemical Society

of natural products and biologically active molecules and their role as useful synthons in organic synthesis.4 Thus, the preparation of O-containing compounds has always been an important topic. Apart from the traditional synthetic protocols, many new catalytic methods have been developed in the last decades. Among them, the incorporation of oxygen atoms from molecular oxygen into substrates using a transition-metal catalyst is one of the most attractive approaches. Our group’s research has been focused on the development of green and efficient aerobic oxidation synthetic methodologies for the synthesis of O- and/or N-containing compounds.5 The present Account summarizes our recent progress on the catalytic aerobic oxygenation of readily Received: March 6, 2017 Published: June 21, 2017 1640

DOI: 10.1021/acs.accounts.7b00108 Acc. Chem. Res. 2017, 50, 1640−1653

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Accounts of Chemical Research

experiments suggested that a peroxide radical may be involved as an important intermediate (Scheme 1c). A radical pathway is depicted accordingly (Scheme 1d). Insertion of the alkyne affords CuII intermediate A, followed by the generation of imine radical B, which is trapped by O2, leading to superoxide radical intermediate C. Subsequently, an intramolecular cycloaddition occurs to give the corresponding aminyl radical D, which undergoes the second deprotonation assisted by TEMPO and/or O2 to afford intermediate E. Finally, fragmentation of E generates the α-keto amide product. However, the above method for the synthesis of α-keto amides from anilines and terminal alkynes has some limitations: (i) Cu-catalyzed homocoupling of terminal alkynes is hard to avoid; (ii) the efficiency of electron-deficient aniline substrates is low; and (iii) the transformation is not applicable to Nsubstituted anilines.7 Hence, on the basis of the catalytic cycle shown above (Scheme 1d), we have developed a CuBrcatalyzed aerobic oxygenation of anilines (1) with aryl acetaldehydes (4) for the synthesis of α-keto amides (3).8 Two Csp3−H bond cleavages, one Csp2−H bond cleavage, and one N−H bond cleavage are involved in this transformation (Scheme 2a). Importantly, electron-deficient anilines performed successfully with this protocol. An orexin receptor antagonist could be prepared from simple and readily available

available substrates, including simple hydrocarbons, for the synthesis of O-containing compounds via C−H or C−C bond cleavage. Emphasis will be placed on the role of dioxygen and mechanistic studies. These transformations will provide a platform for further development of novel oxygenation reactions.

2. OXYGENATION WITH O2 FOR CO DOUBLE-BOND FORMATION 2.1. Synthesis of α-Keto Amides by the Reaction of Anilines with Alkynes or Aryl Acetaldehydes

α-Keto amides are important structural motifs in natural and bioactive products as well as functional materials. In addition, they are valuable synthons in organic synthesis.6 Therefore, the preparation of α-keto amides has attracted considerable efforts.6−8 One of our oxygenation topics is that we achieved the first examples of the oxygenation of anilines (1) and terminal alkynes (2) catalyzed by CuBr2 to produce α-keto amides (3) with O2 as the oxidant and a reactant (Scheme 1a).7 Scheme 1. Cu-Catalyzed Oxidation of Anilines and Terminal Alkynes Leading to α-Keto Amides

Scheme 2. Cu-Catalyzed Oxygenation of Anilines with Aryl Acetaldehydes Leading to α-Keto Amides

A series of electron-rich and electron-poor terminal alkynes underwent the oxygenation process successfully. Good yields were observed with anilines bearing electron-donating substituents. An isotope labeling experiment indicated that both oxygen atoms in the α-keto amide products come from O2 (Scheme 1b). The electron paramagnetic resonance (EPR) 1641


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Accounts of Chemical Research starting materials by this method (Scheme 2b). Isotope labeling results indicated that O2 is the oxygen source (Scheme 2c). A single electron transfer (SET) pathway is proposed (Scheme 2d). The aldehyde and aniline initially dehydrate to form imine A, which undergoes single-electron oxidation and is trapped by O2 to generate peroxide radical B. Then CuII combines with peroxide radical B to form CuIII complex C. Subsequently, the relay of intramolecular addition and N−Cu bond homolysis forms imine radical intermediate D, which is oxidized by CuII or O2 to give intermediate E. Finally, fragmentation of E affords the α-keto amide product.

Scheme 3. Cu-Catalyzed Aerobic Oxidative Coupling of 1,3Diketones with Alcohols Leading to α-Keto Esters

2.2. Synthesis of α-Keto Esters by the Reaction of 1,3-Diones, α-Carbonyl Aldehydes, or Methyl Ketones with Alcohols

α-Keto esters are key constituents in various bioactive molecules as well as versatile intermediates. Many approaches to α-keto esters are already developed, such as electrochemical synthesis from acetophenones, Pd-catalyzed carbonylation, and dehydrogenation of α-hydroxyl esters.9 Despite their significances, these methodologies usually proceed under harsh reaction conditions with low atom economy and require a noble-metal catalyst. The cleavage of C−C bonds is one of the most attractive and challenging topics in organic synthesis. The selective cleavage of C−C bonds catalyzed by transition metals is a useful strategy, providing new synthetic methods for transformations that are difficult to achieve via traditional processes.10 We have developed a Cu-catalyzed oxidative esterification of 1,3-diones (5) with alcohols (6) through C−C σ-bond cleavage and oxygenation with O2 leading to α-keto esters (7).11 This protocol successfully combines C−C bond cleavage, O2 activation, and C−H bond functionalization, providing a practical synthetic method for α-keto esters (Scheme 3a). Androsterone could proceed well to afford a complex α-keto ester molecule (Scheme 3b). The transformation in the presence of 18O2 generated the 18O-labeled product, indicating that the oxygen atom in the formed product originated from O2 (Scheme 3c). A possible radical catalytic cycle is proposed accordingly (Scheme 3d). Initially, Cu-catalyzed oxidative dehydrogenative coupling of the 1,3-dione with the alcohol affords intermediate A, followed by formation of peroxide intermediate B. Subsequently, reduction by the CuI catalyst generates intermediate C. The further addition reaction with another alcohol molecule affords hemiacetal intermediate D. Oxidative fragmentation generates the desired α-keto ester product. Toward the development of a more efficient Cu-catalyzed protocol for the preparation of α-keto esters from simpler starting materials, we have further disclosed an aerobic oxidative dehydrogenative coupling of α-carbonyl aldehydes (8) with alcohols (Scheme 4).12 This atom-economical transformation employing air as a green and practical oxidant afforded α-keto esters with ample scope and broad functional group tolerance under mild reaction conditions.

Scheme 4. Cu-Catalyzed Oxidative Coupling of Carbonyl Aldehydes with Alcohols

aerobic oxidative esterification of simple ketones (9) for the preparation of ester products (10) via C−C bond cleavage was achieved (Scheme 5a).14 A series of common ketones, including inactive aryl long-chain alkyl ketones, could be smoothly transformed. The 18O labeling experiment suggested that oxygenation with O2 occurs during this reaction (Scheme 5b). Two possible pathways are mainly involved in this process (Scheme 5c). Initially, hemiketal A is formed by the nucleophilic addition of the alcohol to the ketone. In pathway

2.3. Synthesis of Esters by Esterification of Ketones with Alcohols

Although the Cu-catalyzed aerobic oxidative C(CO)−C bond cleavage of common ketones has received considerable attention recently,11,13 the aerobic oxidative functionalization of simple ketones through C−C bond cleavage with other types of nucleophiles such as alcohols for esterification reactions remains a challenging task. In this scenario, the Cu-catalyzed 1642


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Accounts of Chemical Research Scheme 5. Cu-Catalyzed Esterification of Ketones with Alcohols To Give Esters

Scheme 6. Cu-Catalyzed Oxygenation of Methyl Ketones with Alcohols

a, the single-electron oxidation and oxygenation generates peroxide intermediate B. Then SET reduction and subsequent protonation generates hydroperoxide intermediate C. Further rearrangement of C leads to C−C bond cleavage, affording the ester product along with the formation of aldehyde F. Alternatively, in pathway b, dehydration of hemiketal A generates vinyl ether D, which can react with CuII and superoxide radical to produce dioxetane intermediate E. Finally, the C−C and O−O bond cleavages of the dioxetane intermediate produce the ester product and aldehyde byproduct F. Since methyl ketones are simple and widely commercially available starting materials, we have further developed a copper/2,2,6,6-tetramethylpiperidine (TEMP)-cocatalyzed oxygenation of methyl ketones (11) with alcohols for the preparation of α-keto esters (Scheme 6a).15 Electron-rich and sterically demanding TEMP is essential in this chemistry. On the basis of control (Scheme 6b) and EPR experiments (Scheme 6c), a proposed mechanism via a SET process is illustrated (Scheme 6d). First, condensation of TEMP with the methyl ketone occurs, giving enamine intermediate A. Oxidation of enamine A by CuII forms iminyl radical intermediate B, which reacts with superoxide radical anion to afford peroxide intermediate C. Subsequently, reduction by CuI produces anion species D along with the formation of hydroxyl radical, after which oxidation by CuII and hydroxyl radical generates α-carbonyl iminyl cation E. Then hydrolysis produces the phenylglyoxal intermediate and regenerates TEMP. Finally,

the reaction of the phenylglyoxal with the alcohol produces the α-keto ester under the copper/TEMP/O2 system.12 2.4. Synthesis of Ketones and Aldehydes by the Oxygenation of Simple Hydrocarbons

The CC double bond widely exists in organic molecules. Oxidative cleavage of the CC double bond has been a longstanding research topic in synthetic chemistry.16 In keeping with our interest in the development of protocols for the synthesis of O-containing compounds through SET processes, we envisioned that the oxygenation of olefins through CC double-bond cleavage could proceed successfully via a radical process. It was found that N-hydroxyphthalimide (NHPI) could be an efficient catalyst for aerobic oxidative cleavage of olefins (12) to carbonyls products (13).17 When α-alkyl aryl ethylenes were tested, the transformations proceeded smoothly to afford ketones as products (Scheme 7a). A radical process is proposed (Scheme 7b). First, phthalimide N-oxyl (PINO) radical A is produced from NHPI. Subsequently, electrophilic addition of PINO radical to the CC bond gives carbon radical intermediate B, which is 1643


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A SET process is proposed (Scheme 8b). First, TMSN3 is oxidized by TEMPO to generate azide radical A along with TEMPO-TMS,20 which was detected by GC−MS. Then radical addition and oxygenation with O2 produces peroxide radical B, after which continuous fragmentation with the release of N2 gives the oxonitrile product. α-Azido ketones and β-hydroxy azides could not be converted to the desired oxonitrile products under the standard conditions, excluding them as intermediates involved in this process. In addition, no N3−TEMPO difunctionalization product of the alkene was detected even with 2 equiv of TEMPO in the absence of O2. Encouraged by our success in the synthesis of oxonitriles shown above, we developed a Cu-catalyzed protocol for the synthesis of oxoamides from amines and unstrained cycloketones via C−C bond cleavage.21 With a dual catalytic approach enlisting gold and iron synergy, substituted heterocycle aldehydes were readily prepared via oxygen radical addition to vinylgold intermediates under Fe catalyst assistance.22 The utilization of natural solar energy is one of the most important challenges in scientific research because of its secure, clean, green, and sustainable character. In connection with our interest in research on aerobic oxidation, we have disclosed an oxygenation of α-aryl halogen derivatives (15) for the synthesis of ketones (16) utilizing visible-light irradiation through the combination of photocatalysis and organocatalysis under air (Scheme 9a).23 Interestingly, pyridinium salt 17, which could

Scheme 7. NHPI-Catalyzed Oxygenation of Olefins

trapped by O2 to furnish peroxide radical C. Then dioxetane species D is produced along with the regeneration of PINO radical to complete the catalytic cycle. Finally, intermediate D undergoes thermal cleavage to afford the carbonyl compound. Inspired by the above-mentioned NHPI-catalyzed oxygenation through the CC bond cleavage, we envisioned that the oxygenation and nitrogenation of olefins5,18 could be realized in the presence of an azide radical under an O2 atmosphere. Interestingly, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) was found to efficiently oxidize TMSN3 to initiate the generation of azide radical and enable the subsequent oxygenation and nitrogenation of simple alkenes (12) for the preparation of oxonitriles (14) via CC bond cleavage (Scheme 8a).19

Scheme 9. Combination of Photocatalysis and Organocatalysis for Oxygenation of Benzyl Halides

Scheme 8. TEMPO-Catalyzed Aerobic Nitrogenation and Oxygenation of Olefins

be isolated in the reaction without the Ru(bpy)3Cl2 catalyst, could be successfully converted to the carbonyl product, indicating that the pyridinium salt acts as a key intermediate in this transformation (Scheme 9b). The isotope labeling experiments with 18O2 clearly indicated that the oxygen atom in the product originates from O2. A SET pathway is proposed for the reaction (Scheme 10). Inspired by the work from the groups of Stahl24a and Sanford24b on Pd-catalyzed aerobic oxidative C−H functionalizations, in which the PdII intermediates are probably oxidized to PdIV via a SET pathway, we envisioned that a PdII intermediate could be oxidized to PdIV by an in situ-generated 1644


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Accounts of Chemical Research Scheme 10. Proposed Mechanism for Oxidation of α-Aryl Halogen Derivatives

Scheme 12. Pd-Catalyzed Aerobic Oxidative C−H Nitration

active radical partner from O2. Subsequently, reductive elimination may occur to afford the desired product, offering new approach for C−H functionalization with O2 as the oxidant (Scheme 11a). Gratifyingly, the reaction of arenes (18) with Scheme 11. Pd-Catalyzed Aerobic Oxidative C−H Acylation with Active Radical Reactants

2.6. Synthesis of Formamides from Formylation of Amines with Aldehydes

Formamides are among the most important functionalities in bioactive compounds. We have disclosed a Mn-promoted synthesis of formamides (23) from amines (21) and aldehydes (22) under aerobic oxidative conditions through C−C bond cleavage (Scheme 13a).27 Mn(OAc)3·2H2O was the most effective transition-metal catalyst. Aldehydes with longer alkyl chains afforded the products in higher yields. The reaction in the presence of 18O2 generated the 18O-labeled product, indicating that the oxygen atom of the formamide product originated from O2. When imine 24 was submitted to the standard reaction conditions, the desired product could be obtained (Scheme 13b), indicating that the imine might be a key intermediate. The data from in situ FT-IR analysis supports the presence of imine (Scheme 13c). The concentration of imine increased quickly at the initial stage of this reaction. Then the signal of imine decreased slowly under the same reaction conditions. Moreover, the peroxide radical intermediate could be detected by EPR spectroscopy. A possible mechanism is illustrated in Scheme 14. The initial dehydration occurs to form imine A, which is oxidized by O2 to afford peroxide radical B through a radical pathway. Subsequently, intramolecular radical addition to the imine gives radical species C, which reacts with imine A to generate intermediate D. Finally, fragmentation of D generates the formamide product.

toluene as the solvent and NHPI as the radical source under Pd catalysis with O2 generated the acylation products (19) successfully (Scheme 11b).25 Furthermore, aryl aldehydes and benzyl alcohols could also be used as acyl equivalents for C−H acylation with O2 as the oxidant.26 By a similar radical strategy, C−H nitration products (20) could be obtained selectively with commercially available tertbutyl nitrite (TBN) and O2 as the precursors of active NO2 radical (Scheme 12a).25 It is noted that pyridine, pyrimidine, pyrazole, pyridol, pyridylketone, oxime, and azo groups can be used as directing groups in this C−H nitration. The 18O labeling experiment (Scheme 12b) indicated that the NO2 radical could be formed by the oxidation of NO radical with O2 through two different processes (Scheme 12c).

2.7. Synthesis of 2-Oxoacetamidines by the Reaction of Aryl Acetaldehydes with Anilines

2-Oxoacetamidines are important units for organic synthesis. Our studies revealed that Cu-catalyzed multiple oxidative functionalization and oxygenation of aryl acetaldehydes (4) with anilines (1) could lead to 2-oxoacetamidine compounds (25).28 The best efficiency was obtained by the use of CuBr as 1645


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Accounts of Chemical Research Scheme 13. Mn-Catalyzed Formylation of Amines with Aldehydes To Give Formamides

Scheme 15. Cu-Catalyzed Synthesis of 2-Oxoacetamidines from Aryl Acetaldehydes and Anilines

Scheme 16. Mechanistic Studies and Proposed Mechanism

Scheme 14. Proposed Mechanism

the catalyst under O2. Six hydrogen dissociations, including two Csp3−H bond activations and one Csp2−H bond activation, were involved in this efficient chemistry (Scheme 15a). This multiple oxidative dehydrogenative functionalization can also be conducted employing two different anilines, delivering unsymmetrically substituted 2-oxoacetamidines (Scheme 15b). The transformation in the presence of 18O2 generated the 18Olabeled product, indicating that the oxygen atom in the 2oxoacetamidine originated from O2 (Scheme 16a). The EPR experiment indicated that superoxide radicals might be key intermediates in this transformation (Scheme 16b).

Although the mechanism is not completely clear yet, a possible mechanism is illustrated in Scheme 16c. Initially, the 1646


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Under the Cu-catalyzed aerobic oxidative conditions, intermediate B could be oxidized to the 2-(1H)-pyridone product. Interestingly, when TMSN3 was employed as the nitrogen source, 3,5-diaryl 2-ketopyridines could be selectively obtained in this Cu-catalyzed oxidative transformation using molecular oxygen as the oxidant.

aldehyde and aniline are dehydrated to give imine A, which can interconvert to enamine B. Subsequently, single-electron oxidation of anilines mediated by CuII occurs to give radical cations C. Then oxidative addition of enamines B with radical cations C under O2 forms radical intermediate D, which can be trapped by O2 to deliver peroxide radical E. Finally, disproportionation of E produces the desired 2-oxoacetamidine. 2.8. Synthesis of 2-(1H)-Pyridones by Cyclization of Aryl Acetaldehydes with Amines

3. AEROBIC OXYGENATION WITH O2 FOR C−OH BOND FORMATION

2-(1H)-Pyridones have been widely found in many biologically active molecules. In continuation of our studies of the reactions of aryl acetaldehydes with amines, we have disclosed a Cucatalyzed cyclization of aryl acetaldehydes (4) with 2-aminopyridines (26) under O2 for the synthesis of 3,5-diaryl-2-(1H)pyridones (27).29 Phenyl acetaldehydes with different substitution patterns on the phenyl ring provided the corresponding 2-(1H)-pyridone products in good yields. 2-Aminobenzothiazole and 2-aminothiazole were also tolerated in this transformation (Scheme 17a). The 18O labeling experiments

3.1. Hydroxylation of Csp2−H Bond

Functionalized 2-(pyridin-2-yl)phenols serve as important structural motifs for the preparation of functional materials and biologically active compounds. The direct hydroxylation of C−H bonds has received tremendous attention because of the industrial importance of phenol products. Stoichiometric oxidants such as PIDA, PIFA, TBHP, and Oxone have been employed. From a practical perspective, the synthesis of phenols via C−H functionalization with O2 is highly desirable.30 The Yu group developed a novel carboxyl-groupdirected C−H hydroxylation with O2 as the oxygen source using benzoquinone as an oxidant.30a Inspired by our previous research on oxidative reactions with O2 via peroxide radical intermediates, we investigated the direct Csp2−H hydroxylation of 2-phenylpyridines (28) and found that the desired orthohydroxylation product (29) could be obtained under O2 using PdCl2 and NHPI as catalysts in toluene (Scheme 18a).31

Scheme 17. Cu-Catalyzed Synthesis of 2-(1H)-Pyridones from Aryl Acetaldehydes and Amines

Scheme 18. PdCl2/NHPI-Cocatalyzed Csp2−H Hydroxylation

Molecular oxygen is used as a reagent and the sole oxidant in the absence of any other stoichiometric oxidant and additive under neutral conditions. Electron-rich as well as electron-poor substrates performed well in this reaction to afford 2-(pyridin2-yl)phenols. The 18O labeling experiment indicated that the oxygen atom in the phenol product originates from O2. The proposed PdII complex was prepared and used as the catalyst in the reaction instead of PdCl2, and the phenol product was formed efficiently (Scheme 18b). The EPR experiments indicated that a hydroxyl radical intermediate might be involved in the reaction. The

demonstrated that both H2O and O2 could serve as the oxygen source (Scheme 17b). A radical process is proposed (Scheme 17c). Initially, Cu-catalyzed condensation of the aryl aldehyde and the amine through an abnormal Chichibabin pyridine synthesis process occurs to generate dihydropyridine intermediate A, which subsequently undergoes oxidative dealkylation to afford 3,5-diphenylpyridinium intermediate B. 1647


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Scheme 20. Cs2CO3-Initiated α-Hydroxylation of Carbonyls

reaction mechanism, especially the valence of the Pd catalyst, is not completely clear yet (Scheme 19). Initially, Pd II Scheme 19. Proposed Mechanism for Hydroxylation of the Csp2−H Bond

intermediate A is formed via pyridine-directed C−H activation. Benzyl radical is generated from toluene through oxidation with PINO and reacts with O2 to give the peroxide radical, which is then transformed to hydroxyl radical and the benzaldehyde byproduct. Subsequently, the combination of hydroxyl radical with PdII intermediate A affords reactive PdIII intermediate B (a PdIV complex cannot be excluded yet). Finally, C−O bond formation via reductive elimination affords the phenol product and regenerates the PdII catalyst. 3.2. Hydroxylation of Csp3−H Bonds To Give Tertiary α-Hydroxyl Carbonyls

Finally, hydroperoxide C could be reduced by P(OEt)3 to provide the alcohol product. The hydroxylation shown above is highly selective for tertiary C−H bonds at the α-position with respect to carbonyls. Secondary Csp3−H bonds could be hydroxylated by our recently developed I2/DMSO system, in which DMSO act as the oxidant and oxygen source for the hydroxyl group.34

Tertiary α-hydroxycarbonyls are important building blocks for organic synthesis and are present in various bioactive molecules. Moreover, they are already widely used as efficient photoinitiators for ultraviolet-cured coatings. A milestone in the field of C−H hydroxylation protocols was achieved by Ritter and co-workers, who used a bimetallic Pd catalyst with O2 as the oxidant and oxygen source to give tertiary α-hydroxycarbonyls with broad substrate scope.32 In the course of our study of Cu-catalyzed aerobic oxidations, we found that the direct α-hydroxylation of carbonyl compounds (30) with O2 toward the formation of tertiary α-hydroxycarbonyls (31) could be simply completed with Cs2CO3 as the catalyst at room temperature under transition-metal-free conditions (Scheme 20).33 It is noteworthy that P(OEt)3 is essential to the reaction, as in the absence of the latter only a trace amount of product was obtained. A variety of tertiary Csp3−H bonds at the αposition with respect to ketones, esters, amides, aldehydes, and β-dicarbonyl compounds could be hydroxylated in excellent yields (Scheme 20a). Significantly, several derivatives of drug substrates, such as ketoprofen, ibuprofen, and naproxen, were found to be compatible with this protocol, providing the corresponding hydroxylated products, thereby demonstrating the potential of this method for drug diversification. The 18O labeling experiment indicated that the oxygen atom of the formed hydroxyl group originates from O2, and P18O(OEt)3 was obtained, indicating that the hydroperoxide intermediate was reduced by P(OEt)3 instead of DMSO solvent.40 A possible mechanism is illustrated (Scheme 20b). First, the substrate undergoes Cs2CO3-initiated deprotonation to produce carbanion intermediate A. Then intermediate A reacts with O2 to give superoxide anion B, which is protonated to afford hydroperoxide C and regenerate intermediate A.

3.3. Synthesis of p-Quinols through Oxygenation of Phenols

Inspired by our previous Cs2CO3/P(OEt)3/O2 protocol for the C−H hydroxylation of carbonyls,33 in which a carbanion intermediate was involved, we hypothesized that parasubstituted phenols could undergo deprotonation by a base to afford phenoxide anions, in which the charge could be transferred to the 4-position, giving a carbanion intermediate. Under aerobic conditions, the carbanion intermediate could react with O2, leading to a hydroxyl group at C-4. To our delight, it was found that multialkyl phenols (32) could be oxidized efficiently by O2 under CsOH/P(OEt)3/DMSO conditions, offering a novel protocol for the preparation of highly valuable p-quinols (33).35 A series of p-quinols were produced with high effiency (Scheme 21a). The 18O labeling experiment indicated that O2 was the oxygen source for the hydroxyl group. A catalytic cycle involving a carbanion intermediate is proposed (Scheme 21b). 3.4. Hydroxyazidation of Olefins to β-Azido Alcohols

β-Azido alcohols are ubiquitous structural motifs in organic molecules. Furthermore, the high-value-added β-azido alcohols can serve as direct precursors of aziridines and β-amino alcohols, both of which are important building blocks in synthetic organic chemistry and widely exist in biologically active compounds. In recent years, transition-metal-catalyzed 1648


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Accounts of Chemical Research Scheme 21. Preparation of p-Quinols by Oxygenation of Phenols with O2

Scheme 22. Mn-Catalyzed Difunctionalization of Alkene

oxidative alkene difunctionalization has become an extremely powerful strategy in organic synthesis, as evidenced by many elegant works. We recently developed a TEMPO-catalyzed synthesis of oxonitriles from the oxygenation and nitrogenation of olefins via CC double-bond cleavage (Scheme 8).19 Inspired by these works, we hypothesized that if the generated peroxide radical intermediate could be stabilized by a transitionmetal catalyst to form a peroxometal complex, then the favorable protonation may happen to give β-azido peroxy alcohols, which could finally produce the corresponding β-azido alcohols by reduction.33 According to the above hypothesis, the reaction was investigated in the presence of H2O. As expected, MnBr2 was found to be an efficient single-electron catalyst for the aerobic oxidative hydroxyazidation of alkenes (12) (Scheme 22). This protocol was found to have a broad substrate scope. Both terminal and internal styrenes in the presence of TMSN3, MnBr2, and H2O in MeCN under air at room temperature performed well to produce the desired β-azido alcohols (34) in high yields. Gratifyingly, unactivated alkenes that were chemically inert in previously reported olefin difunctionalizations performed well under the standard conditions (Scheme 22a). Interestingly, when 2-vinylbenzoic acids (35), which usually undergo lactonization to construct substituted lactones, were used as substrates, unexpected cyclic peroxy alcohol esters (36) were produced (Scheme 22b).36 The results of 18O2 and H218O isotopic labeling experiments showed that O2 was the oxygen source for the hydroxyl group. Density functional theory (DFT) calculations were also performed (Scheme 23). Initially, MnII is easily oxidized to MnIII, which can oxidize TMSN3 to deliver an azide radical, requiring a free energy of 2.0 kcal/mol. The addition of azide radical to indene is facile, with an activation free energy of 6.9 kcal/mol, forming intermediate INT1, which is further trapped by dioxygen to furnish INT2 barrierlessly. Consequently, complex INT3 is produced by reaction of INT2 with the MnII catalyst. Then, complex INT3 is further hydrolyzed to provide the β-azido peroxy alcohol with the formation of MnIII catalyst

Scheme 23. DFT-Computed Energy Profiles for MnBr2Catalyzed Hydroxyazidation

to complete the catalytic circle. Oxidation of TMSN3 by INT2 through a homolytic substitution process to initiate azide radical and offer INT4 is endergonic by 7.9 kcal/mol, indicating that this pathway is disfavored in comparison with the Mncatalytic pathway. Accordingly, a SET process is proposed (Scheme 24). The generated carbon radical B and the MnIII intermediate D are key species for this transformation. 3.5. Oxygenation of Olefins to Alcohols

With a similar protocol as for the radical difunctionalization of alkenes, a catalyst-controlled, highly chemoselective coupling and oxygenation of alkenes (12) with hydrazines (37) for the direct synthesis of alcohols (38) has been developed (Scheme 25a).37 The alcohol product could be selectively obtained when 1649


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Accounts of Chemical Research Scheme 24. Proposed Mechanism

Scheme 26. Selective Synthesis of 1,2-Diarylethanones and 1,2-Diarylethanediones

the reaction was conducted with tetrabutylammonium iodide (TBAI) as the catalyst. Scheme 25. TBAI-Catalyzed Synthesis of Alcohols through Radical Addition

Scheme 27. Direct Synthesis of Tryptophol Derivatives

A SET mechanism is proposed (Scheme 25b). Phenyl radical A is initially generated via a SET process. Addition of A to styrene produces carbon radical B, which is then trapped by O2 to afford peroxide radical C, which abstracts a proton to provide hydroperoxide D. Subsequently, the hydroxylation product could be generated through Landolt reaction. Interestingly, when DABCO was employed as the catalyst, 1,2-diarylethanones (39) could be selectivity generated. Furthermore, 1,2-diarylethanediones (40) could be obtained by a copper/iron cocatalytic system (Scheme 26). 3.6. Reassembly of 2-Vinylanilines and Alkynes to Tryptophols

could be performed in DMSO under an O2 atmosphere without any metal catalyst (Scheme 27a). It is noteworthy that changing the solvent from DMSO to 1,4-dioxane gives rise to the corresponding peroxide tryptophol (44) (Scheme 27b). Thus, the tryptophol products could be effortlessly switched by the selection of the solvent. The 18O labeling experiment demonstrated that the oxygen atom of the hydroxyl group in the product originates from O2, and the reaction of [D2]2-vinylaniline suggests that CC triple-bond cleavage may be involved rather than CC doublebond cleavage (Scheme 28a). Thus, a radical mechanism is illustrated (Scheme 28b). Initially, enamine A is quickly formed by hydroamination of the alkyne with 2-vinylaniline. Subsequently, intramolecular thermal [2 + 2] cyclization occurs to afford intermediate B,

Tryptophols are common building blocks in natural products and pharmaceuticals as well as important intermediates. As previously mentioned, reactions through C−C single-bond and CC double-bond cleavage have attracted considerable attention, but transformations with CC triple-bond cleavage are still a challenging issue. Furthermore, the cleavage and reassembly of a CC triple bond located in one product for the synthesis of more complex compounds has rarely been achieved. With our continuing interest in oxidative oxygenation reactions with O2, we have demonstrated an approach to tryptophol derivatives through a reassembly strategy of 2vinylanilines (41) and alkynes (42) via CC triple-bond cleavage and O2 activation (Scheme 27).38 The optimization of the conditions indicated that the synthesis of tryptophols (43) 1650


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Accounts of Chemical Research Scheme 28. Mechanistic Studies and Proposed Mechanism

Scheme 29. Cu-Mediated Oxygenation for the Synthesis of Oxazoles

oxidized and trapped by O2 to form intermediate B. Then 1,5hydrogen-atom abstraction gives intermediate C. Finally, intramolecular radical coupling and oxidation yield the oxazole product.

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followed by homolytic cleavage of the C−C bond to generate radical intermediate C. Then the secondary carbon radical has priority over the tertiary carbon radical to be trapped by O2, leading to peroxide radical intermediate D. The subsequent intramolecular 1,5-hydrogen atom transfer (HAT) process enables the formation of the peroxide tryptophol (44), which could be successfully obtained in 1,4-dioxane. Finally, the peroxide tryptophol is reduced by DMSO to generate the tryptophol products (43).

SUMMARY AND PERSPECTIVE In this Account, we have summarized our recent research on the oxygenation of readily available substrates with O2 (1 atm or in air) for the synthesis of O-containing compounds. In our efforts to develop green synthetic methodologies, numerous simple and efficient methods for the cleavage of C−H or C−C bonds with O2 have been established. The incorporation of O2 was usually accomplished through transition-metal-catalyzed single electron transfer processes. The mechanistic studies of these reactions revealed that an active radical such as a carbon radical, peroxide radical, or hydroxyl radical is in most cases involved in these oxygenation transformations. On the basis of these developments, enantioselective oxygenations with O2 should also be further developed. Moreover, the incorporation of molecular oxygen into a ring for the direct formation of Ocontaining heterocycles is also very desirable. We expect that a better understanding of the reaction mechanisms will provide more inspiration for the design of new green and atomeconomical oxidative reactions utilizing O2, although safe handling is required for large-scale applications in industry.

4. AEROBIC OXYGENATION WITH O2 FOR C−O−C BOND FORMATION The incorporation of an O atom from O2 into simple substrates to prepare O-heterocycles is still a challenging issue.39 During our studies of the reaction of aldehydes with amines under O2, we found that oxazoles could be selectively obtained through Cu-mediated aerobic oxidative dehydrogenative annulation of aryl acetaldehydes (4) with amines (21) via dioxygen activation (Scheme 29a).40 This reaction is highly efficient, with six hydrogen dissociations, providing a simple and easily operable protocol for the synthesis of 2,5-disubstituted oxazoles (45). The transformation proceeded well with a wide range of amines, including alkyl-substituted amines, and aryl acetaldehydes. Unfortunately, aliphatic aldehydes failed to produce the oxazole products under the standard conditions. Control experiments with benzamide and benzonitrile failed to deliver the product in significant yield, excluding them as intermediates of this transformation. A possible reaction pathway is proposed (Scheme 29b), although detailed studies of the redox reaction of the Cu salt are still needed. Initial dehydration generates imine A, which is

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ning Jiao: 0000-0003-0290-9034 Notes

The authors declare no competing financial interest. 1651


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Accounts of Chemical Research Biographies

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Yu-Feng Liang was born in 1986 in Jiangxi, China. He received his B.S. and M.S. degrees in 2009 and 2012 under the supervision of Prof. Hua-Jian Xu at Hefei University of Technology. Subsequently, he joined Prof. Ning Jiao’s group at Peking University and obtained his Ph.D degree in 2015. Since 2016, he has conducted his postdoctoral research at University of Göttingen with Prof. Lutz Ackermann as an Alexander von Humboldt Postdoctoral Fellow. Ning Jiao received his Ph.D. degree in 2004 with Prof. Shengming Ma at Shanghai Institute of Organic Chemistry (SIOC). He then spent 2004−2006 as an Alexander von Humboldt Postdoctoral Fellow with Prof. Manfred T. Reetz at Max Planck Institute für Kohlenforschung. He joined the faculty at Peking University as an Associate Professor in 2007 and was promoted to Full Professor in 2010. His current research efforts are focused on (1) the development of synthetic methodologies through SET, (2) aerobic oxidation, oxygenation, nitrogenation, and halogenation reactions, and (3) catalysis by firstrow transition metals and activation of inert chemical bonds.

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ACKNOWLEDGMENTS Financial support from the National Basic Research Program of China (973 Program) (2015CB856600), the National Natural Science Foundation of China (21325206 and 21632001), the National Young Top-Notch Talent Support Program, and Peking University Health Science Center (BMU20160541) is greatly appreciated.

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