Manganese(III) acetate in organic synthesis: a review of the past decade

Abstract

Mn(OAc)₃ has emerged as a highly valuable one-electron oxidant in the fields of synthetic and medicinal chemistry, owing to its mild reactivity, economic feasibility, and low toxicity. In recent years, significant advancements have been made in Mn(OAc)₃ chemistry, markedly expanding the boundaries of synthetic radical chemistry. This review offers a consolidated and critical overview of the latest developments and applications of Mn(OAc)₃ in organic synthesis over the past decade. The emphasis is placed on efforts that strive to achieve milder reaction conditions and broaden the range of synthesis opportunities. It is our intention that this review will serve as a valuable reference for the synthetic and medicinal chemistry communities, inspiring further exploration and innovation in this dynamic field.

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Jian Wang

Dr Jian Wang was born in Sichuan (P. R. of China) in 1987. In 2014, he earned his Ph.D. from Sichuan University under the supervision of Prof. Xiaoqi Yu. From 2015 to 2017, he worked as a postdoctoral researcher in Prof. Wu Jishan's group at the National University of Singapore (NUS). Now, he is an assistant professor of organic chemistry in the School of Pharmacy at Chengdu University. His current research interests focus on organic photocatalysis and the synthesis of pharmaceutically active compounds.

Shuai Liang

Prof. Dr Shuai Liang was born in Qingdao (P. R. of China) in 1988. He earned his BS and MS degrees in 2011 and 2014 from Sichuan University, under the guidance of Prof. Xiaoqi Yu. In 2018 he obtained his PhD in organic chemistry from Goethe-University Frankfurt, under the supervision of Prof. Dr Georg Manolikakes. In 2019, he joined the School of Pharmacy, Qingdao University, as an assistant professor. His current research interests focus on synthetic methodology studies of sulfonyl-group containing compounds and their applications in medicinal chemistry.

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1. Introduction

Manganese(III) acetate [Mn(OAc)₃] has been a pivotal reagent in organic synthesis since the 1960s. It is renowned for its role as a mild one-electron oxidant, facilitating the formation of a variety of chemical bonds.¹ Exceptional selectivity and comparatively mild oxidation conditions have established it as a prominent reagent in the synthesis of functionalized molecules. Particularly, Mn(OAc)₃ serves as a highly effective radical initiator, promoting the one-electron oxidation of various functional groups, such as 1,3-dicarbonyls, phosphite, azide and sulfinate.² This versatile process enables the construction of multiple carbon–carbon and carbon–heteroatom bonds under mild conditions, leading to the synthesis of a wide range of novel molecules with potential biological relevance.

Mn(OAc)₃ is a brown powder with a distinct acetic acid (AcOH) odor and can be prepared either by combining Mn(OAc)₂ and KMnO₄ in AcOH or through in situ preparation using Mn(OAc)₂ along with additional oxidants or electrolysis.³ However, the commercially available form of Mn(OAc)₃·2H₂O, with two hydrate molecules, is more commonly utilized due to its superior stability during storage. In most studies, researchers employ Mn(OAc)₃·2H₂O, although the specific form of Mn(OAc)₃ used may not always be explicitly specified. While AcOH typically serves as the preferred solvent for Mn(OAc)₃, alternative solvents such as methanol, benzene, dichloromethane (DCM), and hexafluoroisopropanol (HFIP) can be selected based on the solubility of the substrate. Additionally, the oxidation ability of Mn(OAc)₃ can be adjusted by optimizing the choice of solvent, thereby enhancing reaction efficiency and preventing over-oxidation.

In this review, we focus on advancements in Mn(OAc)₃ chemistry made over the past decade.⁴ The review is organized based on the types of bond formed, with an emphasis on efforts aimed at achieving milder reaction conditions while expanding the scope of synthesis possibilities. Additionally, we provide an in-depth discussion of the reaction mechanisms and potential applications. By summarizing recent progress in this field, our aim is to offer valuable insights into the growing number of applications of Mn(OAc)₃ in organic synthesis and to shed light on the development of more efficient and versatile synthesis strategies. It is worth noting that the chemistry of Mn(acac)₃, a commonly used alternative to Mn(OAc)₃, is also considered within the same scope and described in this review. Moreover, we discuss reactions involving catalytic Mn(OAc)₂/Mn(acac)₂ with the assistance of extra oxidants or electrolysis. Other Mn-catalyzed/promoted reactions, such as the chemistry of Mn(I) or Mn(III)–salen complexes, which represent separate and profound areas of research, will fall outside the scope of this review. Interested readers can find related information in other available review articles.⁵

2. C–C bond formation with 1,3-dicarbonyl and related compounds

Mn(OAc)₃ is widely acknowledged for its remarkable ability to generate electro-deficient carbon-centered radicals from malonates and related 1,3-dicarbonyl compounds, and it has been applied in a number of natural product syntheses. The reaction mechanism involves the formation of Mn(III)–enolate complexes and single electron transfer (SET) between 1,3-dicarbonyl compounds and Mn(III), resulting in the formation of 1,3-dicarbonyl radicals. These radicals are subsequently trapped and participate in intramolecular cyclization or undergo a second oxidation followed by proton loss.^2c The specific outcomes of the reactions depend on the structure of the employed reaction partners. Recent research efforts have focused on expanding the reaction scope to construct novel heterocycles with potential biological relevance.

The Mn(OAc)₃-promoted radical coupling between alkenes and 1,3-dicarbonyl compounds has emerged as a valuable strategy for the formation of diverse heterocycles via tandem C–C radical couplings and C–O cyclizations.⁶ Researchers have extensively explored the potential of this method, with applications ranging from the synthesis of branched carbasugars⁷ to the facile synthesis of butyrolactones.⁸ One widely well-known example is the Mn(OAc)₃ mediated oxidative [3 + 2] reaction between a 1,3-dicarbonyl type substrate and an alkene. The mechanism involves the addition of a 1,3-dicarbonyl radical to the alkene, followed by a second oxidation that generates a cation. This cation is then trapped by one of the oxygens of the carbonyl, resulting in the formation of biologically important dihydrofuran (DHF) and dihydropyran structural moieties.⁹ For example, the Yilmaz group realized the synthesis of dihydrofuropyrimidine derivatives 2 by utilizing microwave irradiation conditions to overcome low substrate solubility in HOAc, resulting in the formation of fused heterocycles with high efficiency (Scheme 1).¹⁰ One of the synthesized heterocycles showed excellent inhibitory potential in a preliminary acetylcholine esterase (AchE) inhibition test. In a similar manner, the same group expanded their investigations to the synthesis of a series of other heterocycles containing DHF moieties, including 4,5-dihydrofuran-3-carbonitrile derivatives,¹¹ piperazine substituted dihydrofurans,¹² and thiophene containing pyranone and quinolinone derivatives.¹³

Scheme 1 Synthesis of dihydrofuropyrimidine compounds. Yilmaz et al.

Alagöz and co-workers developed a convenient method for the preparation of heterocycles containing both DHF and quinone moieties. By utilizing the Mn(OAc)₃-promoted oxidative cyclization of 2-hydroxy-1,4-naphthoquinones 3 and thiophene or furan-substituted alkenes, the desired products 4 were obtained in up to 89% yield (Scheme 2).^14a The authors discovered that under harsher reaction conditions, such as longer reaction times or higher temperatures, the kinetic DHF product was ionized and lost a proton, resulting in the formation of thermodynamically more stable non-cyclized C-alkenylated naphthoquinone products 5. Subsequently, the same research group reported Mn(III)-promoted couplings between 1,3-dicarbonyl compounds and α,β-unsaturated alcohols, leading to the formation of dihydropyran, DHF, and spirocyclic compounds (Scheme 3).^14b The synthesized compounds were screened for their antibacterial activities against various bacteria, revealing that most of the synthesized compounds exhibited greater activity potential than the reference antibiotics, with compound 6 demonstrating the highest antibacterial activity.

Scheme 2 Synthesis of dihydrofuro- and C-alkenylated naphthoquinones. Alagöz et al. (2014).^14a

Scheme 3 Mn(III)-promoted couplings between 1,3-dicarbonyl compounds and α,β-unsaturated alcohols. Alagöz et al. (2018).^14b

The Nishino group has conducted in-depth and comprehensive studies on Mn(OAc)₃ promoted oxidative cyclization with malonates since the 1990s.¹⁵ For example, they investigated the impact of formic acid on the Mn(OAc)₃-promoted synthesis of DHFs, and discovered that the reaction rate was enhanced and the product yield increased when using a mixture of AcOH and formic acid as the solvent. The authors hypothesized that the presence of both ion-pair and cationic Mn(III) species, formed in the solvent mixture, played a crucial role in accelerating the oxidation efficiency.¹⁶

In 2018, Nishino and co-workers realized the oxidative cyclization of alkenes and tricarbonyl systems (Scheme 4).¹⁷ Unlike dicarbonyls, tricarbonyls offered a broader range of product possibilities through 5-endo–trig, 6-endo–trig, or 5-endo–trig cyclizations, resulting in the preparation of diverse dihydropyrans, lactones and bicyclic compounds. The researchers highlighted the significant influence of the nucleophilicity of the carbonyl oxygen in the carbocation intermediate on the cyclization process, as well as the role of both kinetic and thermodynamic controls in determining the outcome of subsequent reactions.

Scheme 4 Synthesis of bicyclic compounds and dihydropyrans. Nishino et al. (2018).¹⁷

The Nishino group also investigated intermolecular couplings between 1,1-diphenyl alkenes and 1,3-dicarbonyls, leading to the formation of diverse functionalized spirocyclic products (Scheme 5). By utilizing 4-acylpyrrolidine-2,3-diones 8 as the coupling partner, the reaction yields 2-oxa-7-azaspiro[4.4]nonane-8,9-diones 9.^18a When N¹,N³-disubstituted malonamides 10 are used as substrates, different products are formed, including iminodihydrofurans, iminodioxaspirononanes, and diazaspirononanes, depending on slight variations in the reaction conditions. The authors conducted comprehensive experimental discussions, isolating and characterizing intermediate byproducts to gain insights into the reaction pathway and selectivity.^18b

Scheme 5 Synthesis of spirocyclic products from 1,1-diphenyl alkenes and 1,3-dicarbonyls. Nishino et al. (2017) & (2022).^18a,b

Furthermore, the same group successfully applied their well-established radical cyclization methods to the synthesis of cyclophane-type macrocycles through the assembly of DHF via intramolecular addition.¹⁹ A notable example is illustrated in Scheme 6, where 2,7-disubstituted naphthalene serves as the starting material. Both 12 and 13 can be obtained, with the product ratio adjustable by varying the reaction conditions. Under optimized conditions, a series of other macrocycles containing phenyl, naphthyl, and dihydrofuran rings were also successfully prepared. Additionally, it is worth mentioning that the Nishino group has recently reported further examples of Mn(OAc)₃-mediated reactions of 1,3-dicarbonyl derivatives, providing further insights into their research endeavors towards the synthesis of DHF and related compounds, as shown in Scheme 7.²⁰

Scheme 6 Synthesis of cyclophane-type macrocycles. Nishino et al. (2016).^19b

Scheme 7 Synthesis of DHF and related compounds. Nishino et al. (2019) & (2021).^20a,b

In 2017, Tu, Zhang and co-workers introduced a modified procedure for synthesizing DHFs from allylic alcohols and 1,3-dicarbonyls (Scheme 8).²¹ They deviated from the traditional use of AcOH as the solvent and instead employed weakly acidic HFIP. The choice of HFIP as a solvent not only enhanced the yield of radical reactions but also eliminated the tedious separation process. As a result, this modification facilitated the functionalization of both the alkene moiety and its allylic position through a sequential process involving S_N2′ nucleophilic substitution and oxidative radical cyclization.

Scheme 8 Synthesis of DHF derivatives in HFIP. Tu, Zhang et al. (2017).²¹

Li et al. reported the Mn(OAc)₃ promoted oxidative coupling of enamides and 1,3-dicarbonyls, resulting in the synthesis of a variety of functionalized DHFs containing amide substitutes in up to 88% yield (Scheme 9).²² Notably, the DHFs obtained could be easily converted into furans or pyrroles through the Paal–Knorr reaction under acidic conditions. Additionally, by substituting the 1,3-dicarbonyl compounds for their 2-substituted counterparts in the reaction with enamides, the researchers achieved the selective production of (Z)-dicarbonyl enamides 19.

Scheme 9 Synthesis of DHFs from enamides and 1,3-dicarbonyls. Li et al. (2014).²²

The Mn(OAc)₃-promoted radical addition of 1,3-dicarbonyls to unsymmetrically substituted alkenes typically results in mixtures containing two regioisomers and two stereoisomers. However, the Balci group discovered that when using alkenes bearing a thiophene unity, this reaction exclusively yielded one single isomer, irrespective of the configuration of the olefins (Scheme 10).²³ This regioselectivity likely depends on the stability of the intermediate radical and cation, with the cation being more stabilized by the electron-rich thiophene. Subsequently, the authors conducted an in-depth investigation to elucidate the observed selectivity through control experiments and calculations. This revealed that in substrates containing a thiophene moiety, the activation barriers played a significant role, potentially due to the interaction between the sulfur atom and Mn, while in substituted stilbene derivatives, both intermediate stability and charge distribution contributed to the observed regioselectivity.

Scheme 10 Regioselectivity observed in the addition of acetylacetone to various alkenes. Balci et al. (2016).^23b

Ferrocene derivatives have found widespread use in synthesis and materials science. In 2017, Aslan et al. developed Mn(OAc)₃ mediated oxidative cyclization reactions of ferrocene substituted alkene and 1,3-dicarbonyl-type substrates, leading to ferrocene substituted DHF and benzofuran derivatives (Scheme 11).²⁴ Interestingly, when using 1,3-dimethylbarbituric acid as the substrate, ferrocene substituted allylidene compounds were obtained instead of the expected furopyrimidine derivatives.

Scheme 11 Synthesis of ferrocene substituted compounds. Aslan et al. (2017).²⁴

Tetrahydrobenzofurans are commonly found in bioactive natural products. In 2015, Mohr et al. reported a Mn(OAc)₃ promoted γ-alkylation/oxa-Michael addition cascade using siloxydienes 27 and 1,3-dicarbonyls 28 (Scheme 12).²⁵ This reaction exhibited complete regiocontrol and excellent stereoselectivity, leading to the formation of sterically congested tetrahydrobenzofuran compounds 29.^25a Building upon this work, the same research group later developed the synthesis of γ-alkylated enones 30 from 27 and 28. This reaction proved to be highly effective at constructing challenging all-carbon quaternary centers through an interrupted form of the formal [3 + 2] cycloaddition.^25a,b

Scheme 12 Synthesis of tetrahydrobenzofurans and related compounds. Mohr et al. (2015).^25a,b

In 2014, Shia et al. developed a novel method utilizing Mn(OAc)₃ for sequential 5-exo–dig and 6-exo/endo cyclization processes to synthesize C-4 functionalized cyclopenta[b]-naphthalene derivatives 32 (Scheme 13).²⁶ This protocol offers a milder alternative to the classic styrenyl dehydro-Diels–Alder (DDA) reaction, which typically necessitates harsh reaction conditions. The reaction has demonstrated excellent compatibility with various functional groups; this is proposed to be attributed to the formation of a Mn(III)–vinyl intermediate with strong covalent characteristics.

Scheme 13 Synthesis of C-4 functionalized cyclopenta[b]-naphthalene derivatives. Shia et al. (2014).²⁶

Çalışkan, Balci and coworkers conducted a series of studies on the Mn(OAc)₃ promoted functionalization of bicyclic systems.²⁷ In 2019, they investigated the Mn(OAc)₃/Cu(OAc)₂ promoted radical addition of active methylene compounds with strained bicyclic alkenes (Scheme 14).^27c The researchers discovered that the nature of the 1,3-dicarbonyl compounds played a crucial role in determining the reaction products. Specifically, when benzonorbornadiene was reacted with 1,3-cyclohexanedione, only the anticipated dihydrofuran derivative was formed. However, when ethyl acetoacetate was used as the reactant, in addition to the expected dihydrofuran derivative, some rearranged side products were also observed.

Scheme 14 Mn(OAc)₃/Cu(OAc)₂ promoted functionalization of bicyclic systems. Çalışkan and Balci (2019).^27c

In addition to synthesizing DHFs, other functionalized heterocycles can be prepared through ingenious substrate designs. The synthesis of quinoline structures can be accomplished through Mn(OAc)₃ promoted inter- or intramolecular cyclization of different γ-amino alkenes and α-carbonyl compounds. In 2013, Chuang et al. successfully developed a straightforward method for constructing functionalized quinolines 36 and 37 using alkenylaryl enamines 35 as starting materials (Scheme 15).^28a This reaction could be achieved by employing either 4 equivalents of Mn(OAc)₃ or a catalytic amount of Mn(OAc)₂ in the presence of Co(OAc)₂ and O₂. The key step in the reaction involves the generation of a peroxy radical intermediate, which is followed by fragmentation to yield the desired products along with the elimination of benzaldehyde. Building upon this work, the same research group expanded the reaction scope to the intramolecular cyclization of alkenylaryl acetamides 38. Consequently, they accomplished the synthesis of 3-substituted 2-quinolinones 39, further enhancing the versatility and utility of this synthetic approach.^28b

Scheme 15 Synthesis of quinoline and quinolinone derivatives. Chuang et al. (2013).^28a,b

In 2016, Chuang and Chen reported the Mn(OAc)₃ mediated synthesis of 3,4-disubstituted quinolin-2(1H)-ones 41via a 6-exo–dig cyclization of α-substituted N-[2-(phenylethynyl)phenyl]acetamides 40 (Scheme 16).²⁹ Notably, molecular oxygen (O₂) played a crucial role in achieving a high yield for this reaction. Consistent with their previous findings, this transformation could also be performed under Mn(II)/Co(II)/O₂ conditions with comparable efficiency. In 2020, Yang, Pan, and co-workers reported a method to synthesize polysubstituted naphthols 43 through Mn(OAc)₃ promoted oxidative coupling of a ketoester and an alkyne (Scheme 17).³⁰ However, this reaction is limited to terminal alkynes, as internal alkynes do not yield successful results.

Scheme 16 Synthesis of 3,4-disubstituted quinolin-2(1H)-ones. Chuang and Chen (2016).²⁹

Scheme 17 Synthesis of polysubstituted naphthols. Yang, Pan et al. (2020).³⁰

In 2020, Zhang and co-workers achieved the synthesis of quinoline-2-carboxylates 45 through a coupling reaction between 2-styrylanilines 44 and acetoacetates in the presence of Mn(OAc)₃ (Scheme 18).³¹ The reaction mechanism involves several key steps, including the formation of a nitrogen-centered radical through H-migration, followed by a cascade intramolecular addition of the nitrogen-centered radical to the C=C double bond, then oxidative deacylation and dehydrogenation. Notably, the authors observed an intriguing chemoselectivity that was regulated by the choice of promoter. When I₂ was used instead of Mn(OAc)₃, the reaction resulted in the formation of 2-alkylquinolines 46 as the product.

Scheme 18 Synthesis of quinoline-2-carboxylates. Zhang et al. (2020).³¹

In 2014, the Burton group developed a diastereoselective synthesis of fused lactone–pyrrolidinones (Scheme 19). This reaction builds upon their previous work on the synthesis of [3.3.0]-bicyclic γ-lactones from substituted 4-pentenyl malonates.³² By utilizing Mn(OAc)₃/Cu(OTf)₂ as promoters, the desired bicyclic products were successfully prepared in good yields with high stereoselectivity through a cascade 5-exo–trig radical cyclization and lactonization process. To demonstrate the versatility of this methodology, the authors carried out the formal synthesis of (−)-salinosporamide A, showcasing its application.^33a Subsequently, the same research group expanded the applicability of this approach to the synthesis of bicyclic tetrahydrofurans using a similar strategy.^33b

Scheme 19 Synthesis of fused lactone–pyrrolidinones. Burton et al. (2014) & (2015).^33a,b

In 2017, Xu, Zhang and colleagues developed a novel synthesis of polysubstituted pyrroles using Mn(OAc)₃ under solvent-free ball milling conditions (Scheme 20).³⁴ This method demonstrated good compatibility with both acetoacetate and 2-phenylacetaldehyde, facilitating smooth reactions with various amines. The key step in this process involves the radical addition of a Mn(III)–enolate species to the in situ generated enamine. It was observed that the reaction would halt at the enamine intermediate when using other oxidants or conducting the reaction in solution. The solvent-free ball milling technique significantly enhanced both conversion rates and reaction yields, while also minimizing side reactions and eliminating the tedious separation procedures required in solution.

Scheme 20 Synthesis of polysubstituted pyrroles. Xu, Zhang et al. (2017).³⁴

Building upon this work, the same research group reported the preparation of 2,3-dihydropyrroles through a multiple-component reaction one year later (Scheme 21).³⁵ In this reaction, a β-enamino ester, which is formed in situ from an amine and an alkyne ester, undergoes tautomerization to form the corresponding β-imine ester. Subsequent single electron oxidation of the β-imine ester with Mn(OAc)₃ generates a C-centered radical, which is then captured by alkenes to initiate a cyclization cascade. In a similar fashion, the authors directly performed the reactions between β-enaminone esters 54 and alkenes. However, the scope of these reactions is limited to β-enaminone esters, as other enaminones in which CO₂Et has been replaced with CH₃ or CF₃ fail to yield the desired product. The authors also demonstrated the one-pot conversion of 2,3-dihydropyrroles into the corresponding polysubstituted pyrroles using K₂S₂O₈.

Scheme 21 Synthesis of 2,3-dihydropyrroles. Xu, Zhang et al. (2018).³⁵

Several novel methods for the synthesis of indole-based compounds have been developed through intramolecular cyclization with malonate derivatives (Scheme 22).³⁶ In 2013, Oisaki and Kanai reported a Mn(acac)₃ catalyzed dehydrogenative cyclization, resulting in the formation of polycyclic indole skeletons. The use of a catalytic amount of Mn(III) instead of stoichiometric or excess Mn(III) oxidants is advantageous, as it not only enhances the overall economy of the reaction but also prevents the cumbersome workup process associated with Mn salts. In this reaction, aerobic oxygen serves as the stoichiometric oxidant, and H₂O is the only stoichiometric side-product.^36a More recently, Zhang and Huang described the chemodivergent synthesis of the indole scaffold. The use of Mn(OAc)₃ promoted intramolecular C–H/C–H couplings, leading to the formation of indeno[1,2 b]indoles, while electrochemical intramolecular C–H/N–H couplings afforded isoindolo[2,1-a]indoles.^36b The Nishino group developed a series of Mn(OAc)₃ promoted methods for the construction of indole derivatives.^36c–e For example, the intramolecular oxidative cyclization of N-aryl-2-oxocycloalkane-1-carboxamides provides a range of spiroindolinones. The obtained spiroindolinones can be readily transformed into alcohols, ring-expanded lactones, and hydrazones, demonstrating their potential as convenient starting materials for the synthesis of natural products.^36e Kerr et al. described the synthesis of pyrroloindoles via a cascade C–N/C–C bond formation between donor–acceptor cyclopropanes and indolines. This process involves the Lewis acid-catalyzed ring opening of donor–acceptor cyclopropanes, followed by a reaction with indolines. Subsequently, a tandem oxidation and intramolecular cyclization process in the presence of Mn(OAc)₃ afforded the desired products. One of these products was successfully applied to the preparation of the skeletal structure of flinderoles.^36f In a similar approach, Punniyamurthy and co-workers demonstrated the synthesis of functionalized benzo-fused indolizines from tetrahydroisoquinolines bearing a pendant malonyl moiety.^36g In 2016, Kim et al. developed a mild synthesis of benzo[a]carbazoles from β-(2-arylindolyl) nitroalkanes using Mn(OAc)₃. The proposed mechanism involves the generation of an α-nitro radical intermediate, which triggers the cyclization cascade, leading to the formation of benzo[a]carbazoles via oxidation or elimination of NO₂.^36h Additionally, Makowiec and co-workers achieved the preparation of 1,2,4-trisubstituted carbazoles from 3-oxoesters through Mn(OAc)₃ promoted cyclization and aromatization processes.³⁶ⁱ

Scheme 22 Synthesis of indole-based compounds.

Kaïm and co-workers reported a Mn(OAc)₃-triggered oxidative dearomatization rection starting from Ugi adducts (Scheme 23).³⁷ This method leads to the formation of seven fused Buchner-type cyclopropanes in the presence of five equivalents of Mn(OAc)₃ in AcOH with up to 71% yield. Interestingly, cyclization occurred through the 6-endo mode instead of the anticipated spirocyclization when substrates with greater steric hindrance were used. However, the starting materials underwent degradation when there were attempts to extend this method to a Mn(III)-catalyzed electrochemical process.

Scheme 23 Synthesis of Buchner-type cyclopropanes. Kaïm et al. (2023).³⁷

The chemical modification of fullerenes can be achieved through Mn(III) promoted radical reactions.^38a In 2019, Liu, Zhang and co-workers reported a Cu(II)/Mn(III)-mediated synergistic radical N-heteroannulation reaction, utilizing N-sulfonylated o-amino-arylmalonates 60, to prepare [60]fullerene-fused tetrahydroquinoline derivatives 61 (Scheme 24).^38b Through theoretical calculations and control experiments, the authors proposed a mechanism in which an unstable biradical species, generated through Cu(II)–Mn(III) co-mediated dehydrogenation, rapidly tautomerized into an aza-o-quinone methide intermediate. This intermediate then undergoes Diels–Alder cycloaddition with C₆₀, ultimately producing the desired product.

Scheme 24 Synthesis of [60]fullerene-fused tetrahydroquinoline derivatives. Liu, Zhang et al. (2019).^38b

Isocyanides have emerged as versatile building blocks for the synthesis of nitrogen-containing heterocycles. The first Mn(III) promoted oxidative cyclization of isocyanide was reported by Tobisu and Chatani in 2012.³⁹ The proposed reaction mechanism involves the intermolecular addition of Mn(III)-initiated aryl or alkyl radicals to 2-isocyanobiphenyls, leading to the formation of imidoyl radicals, followed by oxidative re-aromatization with another Mn(III) oxidant. Inspired by this pioneering work, the Ji group reported the Mn(III)-mediated reaction of 2-isocyanobiaryls 62 with 1,3-dicarbonyl compounds, allowing for the preparation of 6-alkylated phenanthridines 64 and 6-monofluoro-alkylated phenanthridines 65 in up to 80% yield (Scheme 25).⁴⁰ The procedure involves the formation of two new C–C bonds and deacylation via C–C bond cleavage. Furthermore, a mild approach was depicted for the synthesis of mono-fluoromethylated phenanthridine derivatives, achieved through the removal of ester moieties.

Scheme 25 Synthesis of 6-alkylated and 6-monofluoro-alkylated phenanthridines. Ji et al. (2014I).⁴⁰

In addition to its widespread application in intramolecular cyclizations for constructing heterocycles, Mn(OAc)₃ has also been successfully employed as an oxidant for the intermolecular coupling of carbonyl compounds and heteroarenes, facilitating the formation of new C(aryl)–C(alkyl) bonds.^41a,b In 2014, the Yamaguchi group optimized the usage of manganese salts by employing Mn(OAc)₂ in catalytic amounts, along with the addition of NaIO₄ as a terminal oxidant (Scheme 26).^41c This modification enabled the efficient synthesis of α-heteroaryl carbonyl products in up to 94% yield, using a wide range of heteroarenes and carbonyl partners.

Scheme 26 Synthesis of α-heteroaryl carbonyl products. Yamaguchi et al. (2014).^41c

Gribble and co-workers developed a series of Mn(III)-based radical addition reactions involving indoles and carbonyl compounds.^42a,b In 2013, they successfully demonstrated a Mn(III)-mediated oxidative radical addition of malonates to 2-cyanoindoles (Scheme 27).^42b Interestingly, if the initial products contained an enolizable malonate proton, this reaction did not solely result in the direct coupling of indole and malonates, but instead proceeded to a second oxidation step, followed by trapping with acetate. Similarly, Stephenson and co-workers reported a one-pot, three-component coupling reaction involving electron-withdrawing group (EWG) substituted indoles/pyrroles, dimethyl malonate, and AcOH.^42c

Scheme 27 Synthesis of functionalized indoles. Gribble et al. (2013);^42b Stephenson et al. (2016).^42c

In 2018, Gu, Liu, and co-workers conducted a study on the concomitant hydrofunctionalization of alkenols and the oxidation of remote alcohols (Scheme 28).⁴³ Plenty of sulfonyl-, phosphonyl-, and malonate-substituted ketones or aldehydes were successfully prepared through the addition of the corresponding S-, P-, and C-centred radicals to alkenes. Notably, malonate was selected as the C-centred radical precursor, which was generated in the presence of Mn(OAc)₃. The proposed mechanism involved the addition of the corresponding C-centered radicals to alkenes in an anti-Markovnikov fashion, followed by a hydrogen atom transfer (HAT) process. As a result, five malonate-substituted ketone products were obtained in moderate yields.

Scheme 28 Synthesis of malonate-substituted ketones. Gu, Liu et al. (2018).⁴³

In brief, the versatile application of Mn(OAc)₃ for promoting the generation and conversion of α-carbonyl radicals has facilitated the construction of numerous new C–C bonds, leading to the synthesis of diverse functionalized molecules. Significant achievements in this area have been realized over the past decade, largely relying on ingenious substrate designs. Additionally, selectivity issues have been partially addressed by reducing the amounts of Mn(OAc)₃ used and carefully selecting solvents. It is necessary to note that while Mn(OAc)₃ has been widely utilized, it is not the only option for such reactions. Other one-electron oxidants, such as cerium(IV) ammonium nitrate (CAN) and Fe(III),⁴⁴ can serve as viable alternatives to some extent.

However, this classical procedure still faces challenges, necessitating further investigation into a broader range of 1,3-carbonyl compounds and derivatives to achieve the construction of more complex structures. While modifications to the reaction conditions have been implemented, there remains substantial demand for further optimization. The inherent limitations of Mn(III) persist, particularly its narrow tolerance for reducing functional groups and cumbersome workup processes due to the high number of equivalents of Mn(OAc)₃ used.

One promising direction for advancing practical applications is the combination of Mn(III) catalysts with electroorganic synthesis. In 2019, Hilt et al. developed a novel method for Mn(OAc)₃ catalysed electrochemical carbon–carbon bond formation between β-keto esters and silyl enol ethers (Scheme 29).⁴⁵ This approach is significant because it avoids the formation of oxygenated side products, a common issue in Mn(III) promoted reactions, by omitting dioxygen and acidic conditions. As a result, the desired tricarbonyl compounds 77 were prepared in up to 88% yield under mild conditions. Although attempts to control the stereochemistry of the product using chiral manganese catalysts were unsuccessful, the authors demonstrated a possible mechanism through cyclic voltammetry (CV) experiments with a Mn(TPA) complex. It is proposed that the oxidation of the silyl enol ether 76 serves as the initial step in the oxidation process, initiated by a corresponding Mn(IV) species.

Scheme 29 Electrochemical synthesis of tricarbonyl compounds. Hilt et al. (2019).⁴⁵

In another recent report, Vantourout et al. conducted a comprehensive investigation into the Mn-mediated α-radical addition of carbonyls to olefins (Scheme 30).⁴⁶ After systematically studying key reaction parameters such as the pK_a of the carbonyl compound, the substitution and geometry of the alkene, solvent selection, and the amount of Mn(OAc)₃, the authors developed a general set of reaction conditions that proved to be more effective than previous reports, which utilized large excesses of carbonyls in AcOH. Building on these optimization studies, the authors further demonstrated a robust and practical electrocatalytic version of the reaction with an optimal Mn(OAc)₂/AcOH ratio. Another critical factor contributing to the success of this reaction is the use of alternative polarity, which helps prevent the passivation of electrodes caused by the accumulation of Mn-based species on the anode surface.

Scheme 30 Mn-mediated α-radical addition of carbonyls to olefins. Vantourout et al. (2022).⁴⁶

3. C–C bond formation with aryl/alkyl boronic acid and related compounds

The formation of C–C bonds without using a 1,3-dicarbonyl compound in the presence of Mn(OAc)₃ has garnered significant attention in recent decades as a supplementary method for transition-metal catalyzed C–C bond formation reactions. This type of reaction proceeds with a suitable C-centered radical precursor, such as organoboron compounds, under mild reaction conditions and exhibits good tolerance towards various functional groups. Compared to noble metal catalysts like Ru, Rh, and Pd, Mn is a cost-effective and low-toxicity 3d transition metal that is abundantly available in the Earth's crust, thus enhancing its practicality. Furthermore, the radical nature of the process involving Mn(III) enables some of the limitations observed in other methods to be circumvented.

Demir et al. first demonstrated the smooth generation of aryl radicals from arylboronic acids using Mn(III) in aryl–aryl radical coupling reactions.^47a–c Subsequently, the Molander group showcased the alkylation of heteroarenes using potassium alkyl- and alkoxymethyltrifluoroborates.^47d Following these pioneering works, numerous Mn(III)-promoted/catalyzed homolytic aromatic substitution (HAS) reactions with alkyl or aryl organoboron compounds have been developed as efficient methods for constructing various C–C bonds (Scheme 31).⁴⁸ In 2014, Hirano and Miura introduced a C-3-selective direct alkylation and arylation of 2-pyridones with boronic acids. The observed unique C-3 selectivity complements the previously reported C–H activation systems of 2-pyridones using Pd or Ni catalysts.^48a Later, similar site-selective C-3 arylation of quinoxalin-2-ones^48b and C-4 arylation of quinazoline 3-oxide^48c were reported. Additionally, Yuan and Qu developed the C-3 arylation of coumarins^48d and the C-2 arylation of quinoline N-oxide^48e using a KMnO₄/AcOH system. It is noteworthy that even though KMnO₄ was used as the terminal oxidant, the authors proposed that the in situ generated Mn(III) species from Mn(VII) acted as the true promoter in these reactions. In 2015, Dehaen et al. successfully introduced multiple bulky alkyl groups onto boron-dipyrromethene (BODIPY) cores with Mn(OAc)₃, thereby creating a series of solid-state emissive BODIPY dyes.^48f In 2016, the alkylation of unbiased arenes was established as an alternative method for Friedel–Crafts alkylation, through which a variety of polyarenes were converted into the desired products in good yields and selectivity.^48g Ashok and Ilangovan investigated the arylation of 2-aminonaphthoquinone, observing selective C-arylation in the presence of Mn(OAc)₃, while N-arylation was achieved with Ni or Cu catalysts. This catalyst tuning reaction was applied to the synthesis of bioactive benzocarbazoledione from either N-aryl or C-aryl naphthoquinones.^48h

Scheme 31 Mn(III)-promoted/catalyzed homolytic aromatic substitution reactions.

The cascade arylation–cyclization of activated alkenes or alkynes is a highly effective strategy for synthesizing functionalized heterocycles. Pioneering work in this field was conducted by Studer et al. in 2010, who demonstrated the first Mn(OAc)₃ promoted intermolecular aryl radical additions to olefins.^49a This process involves the addition of an aryl radical to an olefin, which can then further react and undergo a HAS process, ultimately leading to the formation of cyclization products (Scheme 32).⁴⁹ In 2015, Tang and co-workers developed a Mn(OAc)₃-mediated arylation–lactonization of alkenoic acids, enabling the simultaneous formation of a C–C bond and intramolecular lactonization in a single reaction. As a result, a wide range of functionalized γ,γ-disubstituted butyrolactones 97 could be prepared in moderate yields.^49b In 2020, the Lei group achieved the synthesis of benzo[4,5]imidazo[2,1 a]isoquinolin-6(5H)one derivatives 99 through Mn(OAc)₃-catalyzed electrochemical cascade cyclization of N-substituted 2-arylbenzoimidazoles 98. Mechanistic investigations revealed that alkyl radicals could be generated directly from alkylboronic acids through anodic oxidation, with the Mn catalyst playing a crucial role in stabilizing the alkyl radical.^49c Furthermore, in 2022, Reddy and coworkers developed a cascade cyclization method for the synthesis of dihydrobenzo[b]fluorenones 101 using 1,6-enynes under mild reaction conditions. This reaction proceeds through a chemoselective 5-exo–trig cyclization, enabling the construction of a complex 6/5/6/6 polycyclic ring system.^49d

Scheme 32 Mn(III) promoted cascade arylation–cyclization.

In 2015, the Tang and Zhao group reported a Mn(OAc)₃ promoted oxidative cyclization of arylacrylamides 102 for the preparation of chloro- and cyano-containing oxindoles (Scheme 33).^50a The key step involves the in situ generation of aryl radicals, which then abstract a hydrogen from DCM or acetonitrile, resulting in the formation of a new alkyl carbon radical. Subsequently, a radical cyclization cascade occurs, leading to the desired products. Building upon this work, Li and co-workers further expanded the scope of the cyclization to ortho-cyanoarylacrylamides, enabling the synthesis of polychloromethyl substituted quinoline-2,4-diones using a similar approach.^50b These methods facilitate the construction of chloro- and cyano-containing heterocycles by leveraging the aryl radical generated from the oxidation of boronic acids with Mn(III) as a valuable promoter.

Scheme 33 Mn(III) promoted cyclization of arylacrylamides. Tang et al. (2015).^50a

Li, Wang, and coworkers realized an oxidative decarboxylative coupling of arylboronic acids and arylpropiolic acids 105, resulting in the synthesis of a series of diaryl 1,2-diketones 106 (Scheme 34).⁵¹ The authors discovered that Mn(OAc)₃ was the most efficient single electron oxidant for this transformation, and the addition of KOAc proved to be beneficial for the reaction. Isotopic labeling experiments revealed that the two oxygen atoms in the resulting 1,2-diketone species were derived from molecular oxygen.

Scheme 34 Synthesis of diaryl 1,2-diketones. Li, Wang et al. (2015).⁵¹

Thioesters and their derivatives are highly valuable structural motifs due to their widespread presence in synthetic chemistry and their diverse range of biological activities. In 2021, Wu et al. reported a Mn(OAc)₃-promoted thiocarbonylation reaction of alkylborates with disulfides, enabling the efficient synthesis of thioesters (Scheme 35).⁵² This process is initiated by SET between Mn(III) and alkyltrifluoroborates, generating alkyl radicals that are subsequently captured by carbon monoxide (CO). The reaction further proceeds through radical couplings between acyl radicals and sulfur radicals, ultimately providing the desired thioester products.

Scheme 35 Mn(OAc)₃-promoted thiocarbonylation. Wu et al. (2021).⁵²

Guo et al. recently described a Mn(OAc)₃-mediated aerobic oxidative denitrative/deboronative C(sp³)–C(sp²) cross-coupling alkylation of β-nitrostyrenes (Scheme 36).⁵³ This method enables the preparation of alkyl–alkenyl coupled olefin products under mild reaction conditions. A wide range of alkylboronic acids and esters were successfully utilized, showcasing the versatility of this approach. Mechanistic investigations provided insights into a reaction pathway involving transmetallation, aerobic oxidation, reductive elimination, and regioselective elimination of the nitrite radical.

Scheme 36 Synthesis of alkyl–alkenyl coupled olefins. Guo et al. (2023).⁵³

Kaur et al. reported a Mn–Cu co-catalyzed radical addition of arylboronic acids to nitriles, leading to the synthesis of a diverse range of symmetrical and unsymmetrical aryl ketones in 60–89% yield (Scheme 37).⁵⁴ The authors proposed that the in situ generated aryl radicals underwent a reaction with the Cu–Bphen activated nitrile intermediate, forming an imine intermediate. Subsequently, hydrolysis of the imine intermediate with water results in the formation of the desired arylketone products.

Scheme 37 Synthesis of aryl ketones. Kaur et al. (2018).⁵⁴

Adib and coworkers demonstrated that Mn(III) species could be generated in situ through the reaction between KMnO₄ and RCOOH under thermal conditions (Scheme 38).⁵⁵ The active Mn(III) species then promotes the acyloxyarylation of various chalcones. Additionally, by subjecting the acyloxyarylated adducts to basic conditions, a more general product, α-arylated chalcones, can be easily obtained through an elimination process.

Scheme 38 Mn(III) promoted α-arylation of chalcones. Adib et al. (2020).⁵⁵

Inspired by Chatani's work in 2012, several research groups independently explored the Mn(acac)₃-promoted synthesis of diverse functionalized N-heterocycles using organic boronic acids and aryl isocyanides. This includes the preparation of 2-functionalized quinolines,^56a indolo[3,2-c]quinoline^56b and 11-functionalized dibenzodiazepines (Scheme 39).^56c Although the desired products vary, the general mechanism operates similarly: in situ generated aryl or alkyl radicals add to aryl isocyanides, resulting in the formation of imidoyl radicals, which subsequently undergo oxidative re-aromatization with another Mn(III) oxidant. These studies highlight the tremendous potential of isocyanides in the construction of various complex nitrogen-containing compounds through the imidoylative annulation mechanism.

Scheme 39 Mn(acac)₃ promoted oxidative cyclization of isocyanides.

In a similar vein, the Xu group reported the Mn(acac)₂-promoted reaction between vinyl isocyanides and boronic acids, leading to the formation of multi-substituted isoquinolines 119 (Scheme 40).^57a The combination of Mn(acac)₂ and O₂ demonstrated a superior performance compared to using Mn(OAc)₃ alone, with O₂ being crucial for oxidizing Mn(II) to Mn(III). Subsequently, the same group extended this cyclization strategy to the reaction of vinyl isocyanides with hydrazines, employing a catalytic amount of Mn(OAc)₂ and utilizing TBPB as the terminal oxidant.^57b In the proposed mechanism, TBPB plays a vital role in oxidizing the Mn(II) catalyst, the phenylhydrazine radical intermediate, and the cyclohexadienyl-type radical intermediate.

Scheme 40 Oxidative cyclization of vinyl isocyanide with boronic acids. Xu et al. (2014) & (2016).^57a,b

In 2018, Wu et al. introduced a radical cyclization strategy for the synthesis of 2-substituted benzothiazoles through cascade C(sp³)–S bond cleavage and imidoyl C–S formation (Scheme 41).⁵⁸ Both organoboronic reagents and H-phosphorus oxides can serve as radical precursors to initiate the reaction. The pivotal step in this reaction involves the addition of an imidoyl radical intermediate to sulfur, followed by the subsequent release of a methyl radical.

Scheme 41 Synthesis of 2-substituted benzothiazoles. Wu et al. (2018).⁵⁸

An interesting study conducted by Alabugin and co-workers focused on the Mn(III)-promoted reaction of o-alkenyl arylisocyanides and boronic acids (Scheme 42).⁵⁹ This reaction follows a cyclization/fragmentation cascade, leading to the formation of C-2 substituted quinoline products 123 when appropriate fragmenting groups are employed. Notably, this report challenges the conventional stereoelectronic restrictions associated with homoallylic ring expansion (HRE) in alkyne cascades. By utilizing alkenes as synthetic equivalents of alkynes, this approach overcomes these limitations and introduces a novel route to the de novo synthesis of substituted quinoline cores.

Scheme 42 Synthesis of C-2 substituted quinolines. Alabugin et al. (2015) & (2017).^59a,b

The Begum group developed the facile construction of quinazoline rings using 1-(azidomethyl)-2-isocyanoarenes 124 as starting materials (Scheme 43).⁶⁰ By employing a Mn(III) oxidant, quinazoline-2-carboxylates can be readily obtained from carbazate precursors. Furthermore, when organoboronic acids are utilized, the reaction leads to the formation of 2-aryl or 2-alkyl quinazolines. Key steps in this process involve the intramolecular cyclization of imidoyl radicals with the azido group, resulting in the formation of a cyclized aminyl radical and the release of N₂. Finally, oxidation facilitated by Mn(OAc)₃ or peroxy radicals leads to the desired products.

Scheme 43 Synthesis of quinazoline-2-carboxylates and 2-aryl or 2-alkyl quinazolines. Begum et al. (2020) & (2021).^60a,b

The Ji group developed cascade reactions employing substrates 127 that contained both isocyanide and carbonitrile moieties (Scheme 44).^61a,b The key intermediate in these reactions is the in situ generated imidoyl radicals through the radical addition of aryl radicals to isocyanides. Subsequently, these imidoyl radicals are intramolecularly captured by cyanide, leading to a continuous cyclization process. Finally, oxidation steps with Mn(III) result in the formation of desired complex heterocycles, including pyrrolopyridines and pyrroloisoquinolines. In another recent report, the same group realized a Mn(acac)₃ catalyzed three-component reaction of o-cyanoaryl isocyanides, arylboronic acids and indole, resulting in the preparation of diverse 2-(1H-indol-3-yl)-2-phenylindolin-3-imines through a nonclassical organometallic-radical mechanism.^61c

Scheme 44 Synthesis of pyrrolopyridines and pyrroloisoquinolines. Ji et al. (2019) & (2019) & (2024).^61a–c

In a similar mechanistic vein, Song et al. realized a Mn(OAc)₃-promoted synthesis of quinolin-3-amines 131 through the oxidative cyclization of 2-(2-isocyanophenyl)acetonitriles 130 with organoboron reagents (Scheme 45).^62a This reaction features a broad substrate scope and excellent compatibility with various functional groups. The resulting quinolin-3-amines have been showcased as versatile building blocks for the modification of bioactive compounds and drug molecules. Building upon this work, Ji and coauthors undertook a related investigation using Mn(acac)₃ as a replacement for Mn(OAc)₃. Notably, this modification led to higher reaction rates and overall yields of the desired products. The authors attributed the improved performance of Mn(acac)₃ to a kinetically controlled process.^62b

Scheme 45 Synthesis of quinolin-3-amines. Song et al. (2021);^62a Ji et al. (2023).^62b

Wang, Li, and co-workers achieved a Mn(III)-mediated radical cyclization of o-alkenyl aromatic isocyanides 132 with boronic acids (Scheme 46).^63a This transformation resulted in the formation of N-unprotected 2-aryl-3-cyanoindoles 133, accompanied by a sequential process involving intermolecular aryl radical addition, intramolecular cyclization, and cleavage of the C–C bond with the elimination of benzaldehyde. The oxygen source in this reaction can be derived from either H₂O or O₂ based on two proposed reaction pathways. In the first pathway, the radical intermediate A is oxidized to a carbocation intermediate, which is subsequently attacked nucleophilically by H₂O. This leads to cleavage of the C–C bond through the elimination of benzaldehyde, yielding the desired products. Another possible pathway, as discussed in Chuang's report (see Scheme 15), involves the addition of O₂ to generate a peroxy radical B, followed by the extrusion of benzaldehyde (Scheme 47). Later, the same research group realized the cyclization reaction of o-acyl aromatic isocyanides, leading to the formation of 3-hydroxyindolenines 134. Notably, this reaction diverges from other Mn(III)-promoted reactions described above, as it does not involve a radical process. Instead, Mn(acac)₃ was employed as a transition-metal catalyst without undergoing an oxidation state change. The cascade process involves transmetalation, nucleophilic addition, and intramolecular cyclization steps.^63b

Scheme 46 Synthesis of 2-aryl-3-cyanoindoles and 3-hydroxyindolenines. Left: Li, Wang et al. (2021);^63a right: Li, Wang et al. (2022).^63b

Scheme 47 Proposed mechanism for the synthesis of 2-aryl-3-cyanoindoles. Li, Wang et al. (2021).^63a

In 2019, Ji's group developed an intermolecular Mn(OAc)₃-mediated radical cascade reaction of boronic acids with isocyanides for the synthesis of amide or diimide derivatives (Scheme 48).^64a The proposed key intermediate in this transformation is the N-phenylnitrilium intermediate, which forms through the oxidation of the imine radical. Following a similar approach, Li et al. reported a Mn(OAc)₃-promoted transnitrilation reaction using arylboronic acids and trityl isocyanide. The different performance of trityl isocyanide in this reaction can be attributed to both steric hindrance and the good leaving ability of the trityl group.^64b

Scheme 48 Mn(OAc)₃ promoted intermolecular radical reaction with isocyanides. Left: Ji et al. (2019);^64a right: Li et al. (2022).^64b

Trifluoromethylation has emerged as a topic of significant interest in recent years due to the unique bioactivities associated with fluorinated compounds. Langlois’ reagent (CF₃SO₂Na) has gained widespread acceptance as a reliable source of CF₃ radicals for introducing trifluoromethyl groups into various molecules. The Zou group reported the trifluoromethylation of several heteroarenes, including coumarins, quinolinones, pyrimidinones, and pyridinones. Importantly, these reactions occur under mild conditions in the presence of air and exhibit good selectivity, yielding the desired products in up to 84% yield (Scheme 49).⁶⁵ The reaction mechanism involves the oxidation of CF₃SO₂Na by Mn(III) to generate CF₃ radicals, which subsequently undergo a HAS process to form new C–C bonds. Interestingly, the researchers observed a decrease in yield with increasing temperature, which could be attributed to the self-coupling of CF₃ radicals at higher temperatures. Furthermore, the authors found that the introduction of steric hindrance had a notable impact on the reaction yield.

Scheme 49 Trifluoromethylation of heteroarenes. Zou et al. (2014).^65a,b

Considerable progress has been made in the Mn(III)-catalyzed/promoted dual functionalization of olefins for the synthesis of molecules containing CF₃ groups in the past decade. The key step in this process involves the addition of a trifluoromethyl radical to C=C double bonds. By utilizing a suitable hydrogen or halogen donor, hydrotrifluoromethylation or halotrifluoromethylation can be achieved (Scheme 50).^66a,b Additionally, the successful preparation of β-trifluoromethylated azides has been accomplished with TMSN₃.^66c In 2020, Wan et al. reported a Mn(acac)₃-catalyzed photoredox hydroxy-trifluoromethylation. The authors discovered that the reaction did not proceed in the absence of light, suggesting that visible light irradiation facilitated the generation of the excited state, Mn³*, required for the production of CF₃ radicals.^66d Furthermore, it was demonstrated that other Mn salts, such as MnCl₂ or MnO₂, could catalyze the aerobic oxytrifluoromethylation of styrenyl olefins in the presence of air.^66e,f

Scheme 50 Dual functionalization of olefins with CF₃SO₂Na.

In 2020, the Shen group developed the Mn(OAc)₂/TBHP-promoted synthesis of tri(di)fluoromethyl-substituted alcohols through radical C–Si bond activation of their own designed fluorinated organosilicon reagents (Scheme 51).⁶⁷ A variety of fluoroalkyl alcohols were prepared via allylation, alkylation, and alkenylation reactions. The reaction mechanism involves ligand exchange between Mn(III) species and an alcohol, followed by homolysis to generate an alkoxyl radical and Mn(II) intermediate. The carbon radical is then formed via Brook rearrangement, which subsequently undergoes further reactions to yield the desired product. Following this, a desilylation work-up using TBAF enables isolation of the alcohol product.

Scheme 51 Synthesis of tri(di)fluoromethyl-substituted alcohols. Shen et al. (2020).⁶⁷

The formation of C–C bonds has always been one of the most important themes in synthetic chemistry. Currently, reactions facilitated or catalyzed by Mn(OAc)₃ have become one of the most commonly used methods to construct C–C bonds in organic synthesis, offering an effective alternative to noble metal catalysts. To date, 1,3-dicarbonyls, organoboron compounds and Langlois’ reagent have successfully served as carbon radical precursors, enabling the construction of various novel molecules under mild conditions. However, there is still a need for the development of additional carbon radical precursors. In this context, the stability of in situ generated radicals and their compatibility with the oxidative environment of Mn(III) present challenges. These challenges can be addressed to some extent by precisely controlling the oxidative capability of Mn(III). One approach is to introduce extra ligands into the reaction system. However, caution is warranted when doing this, as experience has shown that the introduction of ligands can inhibit the SET process in some reactions. Another promising strategy involves combining Mn(OAc)₃ with electrochemical or photochemical systems, while ensuring that the reaction conditions are compatible with the functional groups of the substrates.

4. C–O bond formation

The Mn(OAc)₃ mediated acetoxylation of enones has been recognized as a practical method for the preparation of α′-acetoxy ketone moieties since the 1970s.⁶⁸ This reaction proceeds through a typical radical mechanism, in which the key step is Mn(III) promoted α-carbonyl radical generation. The overall mechanism shares similarities with the general mechanism described in previous sections, with the distinction being the formation of a C–O bond instead of a C–C bond (Scheme 52).

Scheme 52 Mn(OAc)₃ mediated acetoxylation of enones.

Terent'ev and co-workers reported several oxidative couplings promoted by Mn(OAc)₃ or KMnO₃ involving 1,3-dicarbonyls (and heteroanalogues) with various N–O compounds, including oximes, N-hydroxyimides, hydroxamic acids and N-hydroxybenzotriazoles (Scheme 53).⁶⁹ These reactions have demonstrated high efficiency, yielding a wide range of C–O coupling products in good to excellent yields. The proposed mechanism suggests that the reaction proceeds through a radical coupling between nitroxyl or iminoxyl radicals, which are generated from the oxidation of Mn(III), and α-carbonyl radicals via the well-established one-electron oxidation of the dicarbonyl compound.

Scheme 53 Oxidative couplings with N–O compounds. Terent'ev et al. (2013) & (2014) & (2022).^69a–c

In 2018, Deb and coworkers reported a cobalt-catalyzed sp² C–H acetoxylation of benzoic acid derivatives (Scheme 54).⁷⁰ This approach led to the successful synthesis of a diverse range of acetoxylated products, showcasing good tolerance towards plenty of functional groups. The reaction mechanism involves the coordination of Co(II) with the bidentate 8-aminoquinoline directing group present in the substrate. Mn(OAc)₃ has dual roles as both an oxidant, facilitating the formation of Co(III), and as a source of acetoxy in this reaction. Subsequently, ortho-Csp² activation occurs, leading to the formation of a bis-chelated metallacyclic complex. Finally, reductive elimination takes place, resulting in the formation of the corresponding product.

Scheme 54 C–H acetoxylation of benzoic acid derivatives. Deb et al. (2018).⁷⁰

In 2020, the Nishino group demonstrated the selective synthesis of spiro dihydrofurans 155 and dispiro cyclopropanes 156 through the Mn(OAc)₃ promoted intramolecular cyclization of tetracarbonyl compounds (Scheme 55).⁷¹ This reaction involves the generation of carbonyl radicals, which can undergo two distinct pathways. Notably, when the reaction is conducted in a protic solvent at room temperature, it predominantly yields spiro dihydrofurans through C–O couplings. Conversely, in an aprotic polar solvent at reflux temperature, the reaction selectively produced dispiro cyclopropanes via C–C coupling.

Scheme 55 Synthesis of spiro dihydrofurans and dispiro cyclopropanes. Nishino et al. (2020).⁷¹

Another possible reaction pathway after the generation of α-carbonyl radicals involves the capture of molecular oxygen to form hydroperoxide. Organic peroxides are highly valuable structures that serve as privileged scaffolds in various chemical syntheses and radical chemistry. Their reactive O–O bond grants them exceptional versatility as intermediates. Extensive studies on this topic have been conducted by Nishino and colleagues over the past few decades.^15,72 Notably, this type of O₂ insertion has found wide applications in total synthesis endeavors. For example, in the total synthesis of (±)-yezo'otogirin C, the tricyclic core was constructed using an oxidative cascade cyclization strategy involving Mn(II)/Mn(III) and O₂.^73a In 2021, Marti et al. described the multidecagram scale synthesis of endoperoxides in the presence of Mn(OAc)₃ and O₂, highlighting the technical solutions adopted to ensure both safety and productivity under mild conditions.^73b

The synthesis of heterocycles that incorporate a quinoline core is of great interest due to the potential discovery of novel biologically active compounds. 4-Hydroxyquinolin-2(1H)-ones serve as suitable reagents for the construction of a complex quinoline core via Mn(III)-based peroxidation and dihydrofuranation reactions. In 2014, the Nishino group provided a comprehensive description of their findings regarding the oxidation of a mixture of 1,1-disubstituted alkenes and 4-hydroxyquinolinones 157 (Scheme 56).⁷⁴ This oxidation process resulted in the formation of various types of quinolinone derivatives, with the specific derivatives formed being dependent on the substrate structures and reaction conditions. The Mn(III)-catalyzed aerobic oxidation yielded bis(hydroperoxyethyl)quinolinones and azatrioxa[4.4.3]propellanes, while the Mn(OAc)₃-mediated oxidation led to furo[3,2-c]quinolin-4-one analogues.

Scheme 56 Reaction of 1,1-disubstituted alkenes and 4-hydroxyquinolinones. Nishino et al. (2014).⁷⁴

In 2016, Makino et al. introduced a highly effective catalytic system utilizing Mn(acac)₃ for the aerobic hydroperoxidation of styrene and enynes under mild conditions (Scheme 57).⁷⁵ This approach showcased the ability to achieve the oxidative addition of NHPI, HOBt, or NHS to conjugated alkenes, with O₂ from air serving as both the reactant and the terminal oxidant. One intriguing aspect of this research was the remarkable efficiency of the reaction, which proceeded smoothly even with an exceptionally low catalyst loading of Mn(acac)₃, as low as 0.001 mol%.

Scheme 57 Hydroperoxidation of styrene and enynes. Makino et al. (2016).⁷⁵

The same group later reported a highly efficient catalytic oxidative cyclization of unsaturated oximes 159 using Mn(acac)₃, leading to the formation of 4,5-dihydroisoxazoline alcohols 160 (Scheme 58).⁷⁶ A low loading of Mn(acac)₃ (typically 0.1–0.2 mol%) is sufficient to facilitate the smooth progression of the reaction, incorporating molecular O₂ from the air without the need for any additional additives. The reaction mechanism involved the oxidation of oxime by Mn(OAc)₃, followed by the addition of a N–O radical to the alkene, with the resulting radical being terminated by O₂ from air.

Scheme 58 Synthesis of 4,5-dihydroisoxazoline alcohols. Makino et al. (2016).⁷⁶

Heterocyclic endoperoxides, such as 1,2-dioxane, are recognized to be remarkably effective anti-infectious and potent antimalarial compounds. In 2017, Vanelle et al. investigated the peroxycyclization reaction between 2-hydroxy-3-methylnaphthoquinone 161 and various alkenes using subcatalytic amounts of Mn(OAc)₃ under aerobic conditions (Scheme 59).⁷⁷ The presence of the 3-methyl group in naphthoquinone significantly influenced the reactivity of Mn(OAc)₃, serving as an important parameter that led to different reactivity compared to the similar reaction depicted in Scheme 2. Notably, stereoselectivity was observed when employing monosubstituted alkenes. The authors elucidated that this stereoselectivity was attributed to the differing stability of diastereoisomers, wherein the less stable diastereoisomer underwent an acid-catalyzed rearrangement leading to the formation of ring-opened products.

Scheme 59 Synthesis of heterocyclic endoperoxides. Vanelle et al. (2017).⁷⁷

In other research conducted by the Nishino group, they described the Mn(III)-catalyzed aerobic oxidation of 2-alkenyl-1,3-diketone enols, allowing for the efficient synthesis of 1,2-dioxinols in up to 99% yield under mild conditions (Scheme 60).⁷⁸ The versatility of this reaction was demonstrated by its successful application to the synthesis of the natural product phytohormone G3 and its analogs. Furthermore, the resulting 1,2-dioxin-3-ol compounds were easily converted into acetals using various alcohols while preserving the essential endoperoxide bond.

Scheme 60 Synthesis of 1,2-dioxinols. Nishino et al. (2022).⁷⁸

Mn(OAc)₃ has emerged as a valuable transition metal catalyst for the generation of peroxide radicals from organic peroxides. In 2015, Terent'ev et al. developed a Mn(OAc)₃–TBHP promoted bisperoxidation of styrenes, enabling the synthesis of vicinal bis(tert-butyl)peroxides (Scheme 61).⁷⁹ Although various Mnⁿ⁺ salts in different oxidation states are found to be effective catalysts, Mn(OAc)₃ has demonstrated the highest efficiency in this reaction.

Scheme 61 Synthesis of vicinal bis(tert-butyl)peroxides. Terent'ev et al. (2015).⁷⁹

In 2020, Gnanaprakasam and co-workers described a mild and efficient method for the direct C–H peroxidation of 9-substituted fluorenes, C3-substituted 2-oxindoles, and the vicinal bisperoxidation of olefin derivatives (Scheme 62).⁸⁰ To enhance the reaction yields, 2,2′-bipyridine ligands were employed in conjunction with a catalytic amount of Mn(OAc)₃. The introduction of these ligands facilitated the formation of an active and stable bipyridine-based Mn complex, promoting selective radical formation through association and dissociation pathways. To address the potential explosive hazard associated with peroxides, the authors conducted the peroxidation reactions in continuous flow, ensuring improved safety throughout the process. Additionally, they performed a Sn(OTf)₂-catalyzed rearrangement of the synthesized peroxides, leading to the formation of valuable chromene derivatives.

Scheme 62 Synthesis of quaternary peroxides. Gnanaprakasam et al. (2020).⁸⁰

Li and Lv reported a Mn(OAc)₃-catalyzed remote C(sp³)–H bond peroxidation, enabling the efficient synthesis of a variety of 1,6-difunctionalized products 174 with good regioselectivity and functional group compatibility (Scheme 63).⁸¹ The reaction proceeds through a radical relay strategy, involving the addition of electrophilic CF₃ radicals (generated from CF₃SO₂Na) to C=C double bonds. Subsequently, an intramolecular 1,5-HAT reaction occurs, leading to the formation of remote C-centered radicals. These radicals were then selectively trapped by Mnⁿ⁺¹OOtBu species, resulting in the desired products under mild reaction conditions. Notably, tBuOOH played a dual role as both the oxidant and the peroxyl precursor in this reaction.

Scheme 63 Mn(OAc)₃-catalyzed remote C(sp³)–H bond peroxidation. Lv, Li et al. (2021).⁸¹

Li and co-workers conducted a study on the synthesis of functionalized oxazoles 176 from 2-amidodihydrofurans 175 in the presence of Mn(OAc)₃ under air (Scheme 64).⁸² Based on control experiments and electron paramagnetic resonance (EPR) studies, a tentative mechanism was proposed by the authors. Initially, the 2-amidodihydrofuran undergoes alkali-induced ring opening, forming carbanion 177, which is further converted into an alkyl radical in the presence of Mn(OAc)₃. This radical reacts with O₂ in the air, resulting in the formation of a peroxide intermediate. Subsequently, the peroxide intermediate is transformed into an allene, possibly triggered by heat or a base, followed by an intramolecular annulation process that ultimately yields the desired functionalized oxazoles.

Scheme 64 Synthesis of functionalized oxazoles. Li et al. (2017).⁸²

The oxidation of β-keto esters promoted by manganese(III) under aerobic conditions has been established as an efficient method for synthesizing δ-hydroxy-β,γ-unsaturated-α-keto esters. However, this conversion typically required a stoichiometric amount of manganese(III). In a study conducted by Koo et al., it was discovered that the oxidation process could become catalytic by employing a manganese/cobalt co-catalytic system (Scheme 65).⁸³ The reaction is applicable under aerobic conditions and results in the formation of α-oxo esters 179. These α-oxo esters can further undergo additional heterocyclizations, either through intramolecular Diels–Alder reactions leading to the formation of dihydropyrans 180 or through aromatic cyclizations resulting in the formation of furans 183. The specific type of heterocyclization that occurs is dependent on the substitution pattern at the δ-carbon.

Scheme 65 Synthesis of dihydropyrans and furans. Koo et al. (2014).⁸³

Recently, the Nishino group reported an unexpected oxidative cyclization reaction involving methylenebis-(cyclohexane-1,3-dione) enols 184 under aerobic conditions in the presence of Mn(OAc)₃ (Scheme 66).⁸⁴ The researchers proposed that the observed formation of chromene products 185 occurred through the intermediacy of an unstable oxecine species 186, followed by a subsequent Claisen/retro-Claisen reaction in an aqueous environment. Notably, the authors observed that the aerobic oxidation of the enol lacking an R substituent did not proceed successfully.

Scheme 66 Rearrangement of methylenebis(cyclohexane-1,3-dione) enols. Nishino et al. (2022).⁸⁴

5. C–P bond formation

Mn(OAc)₃ promoted phosphonation of unsaturated bonds through SET with phosphinylidene P(O)H compounds has been extensively investigated for the past two decades, with Ishii being a pioneer in this field.⁸⁵ This powerful methodology has demonstrated its versatility by enabling the successful phosphonylation of diverse substrates, including (hetero)arenes, (substituted)alkenes, and more, using a wide range of P–H compounds, such as H-phosphites and H-phosphates. As a result, Mn(OAc)₃ promoted phosphonation has emerged as a valuable synthetic tool for the preparation of various organophosphorus compounds, including phosphonates, phosphinates, and phosphine oxides.

Over the past decade, numerous researchers, such as Montchamp,⁸⁶ Zhao, and Zou, have made significant contributions to this area of study. The underlying reaction mechanism is well-established and involves the oxidation of P–H bonds in phosphinylidene by Mn(III), resulting in the formation of phosphorus radicals. These radical intermediates then undergo various types of radical reactions, such as addition, substitution, or cyclization, in a manner similar to that of other radical reactions. To achieve the desired product, the presence of additional Mn(OAc)₃ is necessary. Consequently, in most reactions, more than two equivalents of Mn(OAc)₃ are required. However, it is possible to optimize the reaction by employing catalytic amounts of Mn(II)/Mn(III) in conjunction with other oxidants. The specific reaction type, rate, and conditions are largely dependent on the intrinsic properties of the P–H compounds and the radical acceptors.

A diverse array of (hetero)aromatic compounds can be efficiently transformed into their corresponding phosphonated products in the presence of Mn(OAc)₃ through the homolytic aromatic substitution (HAS) process.⁸⁷ Over the past decade, significant efforts have been focused on expanding the reaction scope, particularly in the synthesis of biologically active organophosphorus compounds (Scheme 67).⁸⁸ For instance, Kim reported a Mn(OAc)₃ promoted oxidative cross-coupling between uracil and dialkyl phosphites, resulting in the synthesis of various 5-phosphorylated uracil derivatives.^88a Wang and co-workers demonstrated a solvent-free reaction between benzothiazole/thiazole derivatives and organophosphorus compounds under ball-milling conditions in the presence of Mn(OAc)₃.^88e Additionally, Mn(OAc)₃ proved to be effective at converting other heterocycles, such as pyridinones, pyrimidinones, aromatic azo compounds, imidazo[1,2-a]pyridines, pyrrolopyrimidines, indoles, indazoles, and indolizines, into the desired products.

Scheme 67 Synthesis of phosphonated heteroarenes.

In addition to these achievements, several optimized methods have been developed with the aim of reducing the amount of Mn(OAc)₃ used (Scheme 68).⁸⁹ Montchamp introduced a procedure utilizing catalytic Mn(OAc)₂ and excess Mn(IV) as the stoichiometric oxidant. Compared to commonly employed Mn(OAc)₃, the use of the Mn(II) + Mn(IV) combination is cost-effective and robust, which enhances its applicability and scalability. They also demonstrated the direct intramolecular arylation of various phosphinylidene compounds under Mn(III)-promoted or Mn(II) + Mn(IV) conditions, resulting in the formation of phosphonated heterocyclic products.^89a–c Yotphan reported a similar protocol employing K₂S₂O₈ as the terminal oxidant for the regioselective direct C3-phosphinoylation of 2-pyridones.^89d In 2021, the Lei group reported an electrooxidative C–P formation between electron-rich aromatics and diphenyl phosphine oxides.^89e This catalytic reaction serves as an advancement of the work by Zou and Zhang in 2006,^89f eliminating the need for chemical oxidants and offering a convenient and environmentally friendly approach.

Scheme 68 Mn(II) or Mn(III) catalytic phosphonation of arenes.

Phosphorus radicals exhibit the ability to add to unsaturated double or triple bonds, subsequently forming carbon-centered radical intermediates. These intermediates can undergo reaction through several distinct pathways depending on the reaction conditions, resulting in the formation of various acyclic or cyclic phosphonated products (Scheme 69).^89c,90 One notable example is the research work by Zhang et al., who demonstrated the regio- and stereoselective addition of phosphonyl radicals to glycals. The reaction was promoted by Mn(OAc)₂, which was directly oxidized to Mn(III) under ambient air conditions. This method enabled the synthesis of metabolically inert phosphonated sugars in up to 92% yield.^90a

Scheme 69 Hydrophosphorylation of olefins.

The oxyphosphorylation of styrenes proceeds through the interaction of carbon-centered radical intermediates with O₂, resulting in the formation of peroxy radical intermediates 191. Subsequent proton abstraction and dehydration lead to the generation of β-ketophosphonate products 190. This transformation can be achieved under Mn(OAc)₃-promoted^90c or Mn(acac)₃-catalyzed conditions (Scheme 70).^91a Additional investigations by the Zou group revealed that the reactions of styrenes bearing ortho-electron-withdrawing groups, or possessing α- or β-substituents, afforded selective β-hydroxyphosphine oxide products.^91b It is observed from experimental results that the selectivity of this reaction is influenced by both steric hindrance and the electron-withdrawing effects of the substituent groups.

Scheme 70 Oxyphosphorylation of styrenes.

The β-ketophosphine oxide products can also be synthesized from vinyl azides in the presence of a catalytic amount of Mn(acac)₃, as described by Yu and Chen in 2017 (Scheme 71).^92a The authors proposed a possible mechanism involving the generation of a phosphonated iminyl radical as the key step. This intermediate is then reduced by Mn(II) species and subsequently protonated to form an imine intermediate and regenerate Mn(III). Eventually, the hydrolysis of the imine intermediate leads to the desired products. In the same year, Yu and coworkers developed a Mn(OAc)₃-promoted oxidative phosphonylation of N,N-dimethylenaminones 194. This reaction involves the continuous cleavage of the C_sp²–C_sp² bond and the formation of a C_sp³–P bond, resulting in the preparation of β-ketophosphonates via the loss of a molecule of N,N-dimethylformamide (DMF).^92b

Scheme 71 Synthesis of β-ketophosphine oxide from vinyl azides.

In 2015, the Zou group realized a Mn(OAc)₃-promoted phosphonyl radical addition to β-nitrostyrenes, resulting in the formation of (E)-2-alkenyl phosphonates (Scheme 72).^93a This reaction occurs through a radical process, where Mn(OAc)₃ serves as the initiator for the generation of phosphonyl radicals from dialkyl phosphites. The phosphonyl radicals exhibit selective addition to the β-position of nitrostyrenes, followed by the elimination of the NO₂ radical, leading to the formation of the desired products. Notably, the Zou group also successfully applied similar reaction strategies to the radical substitution of β-bromostyrene and α,β-unsaturated sulfones.⁹³

Scheme 72 Synthesis of (E)-2-alkenyl phosphonates. Zou et al. (2015) & (2015) & (2017).^93a–c

In 2018, Zhang and Xiong successfully demonstrated the Mn(acac)₃-promoted phosphorylation of enamides and phosphine oxides, leading to Z-selective β-phosphorylated enamides (Scheme 73).^94a The obtained product could be further reduced and hydrolyzed to form β-aminophosphine. Density functional theory (DFT) studies indicated that the formation of Z-products was significantly influenced by the presence of an intramolecular hydrogen bond. In the same year, the Zou research group also achieved a similar phosphorylation of enamides using Mn(OAc)₃ as the oxidant.^94b

Scheme 73 Synthesis of β-phosphorylated enamides. Zhang, Xiong et al. (2018);^94a Zou et al. (2019).^94b

Aldehyde hydrazones are a unique class of compounds that hold significant synthetic value in organic chemistry. In 2021, the Zou group introduced a convenient one-pot approach for the Mn(OAc)₃-mediated phosphinoylation of aldehyde hydrazones using diphenylphosphine oxide (Scheme 74).⁹⁵ This strategy enables the direct formation of a variety of functionalized α-iminophosphine oxides. Notably, the aldehyde hydrazones are generated in situ from readily available aldehydes, eliminating the need for a separate isolation step.

Scheme 74 Synthesis of functionalized α-iminophosphine oxides. Zou et al. (2021).⁹⁵

Anther common reaction pathway after the addition of phosphorus radicals to double or triple bonds involves the further oxidation of the carbon-centered radical intermediates generated in the presence of excess Mn(III), leading to the formation of a cationic intermediate. This cationic intermediate can either undergo deprotonation, leading to substitution or addition products, or engage in intramolecular nucleophilic cyclization with a suitable nucleophile. Based on this strategy, several dual functionalization reactions of olefins have been successfully established, enabling the installation of two functional groups in a single step. This approach proves to be highly valuable in accessing β-substituted phosphorus compounds that are of potential interest in synthetic and biological chemistry (Scheme 75). The introduction of hydroxy,^96a halogen,^96b azide,^96c and acetyl groups^93c can be achieved smoothly under Mn(OAc)₃-promoted or catalyzed conditions. However, for cyanation^96d or thiocyanation^96e processes, an additional copper catalyst is required to facilitate the reaction.

Scheme 75 Dual functionalization reactions of olefins.

The intramolecular cyclization of the carbon-centered radical intermediates generated facilitates the formation of cyclic products. These cascade transformations provide a convenient one-step pathway that enables the consecutive formation of C–P and C–C/C–O bonds in one pot, ultimately leading to the synthesis of a diverse array of phosphonated heterocycles. In 2013, Miura and co-workers successfully demonstrated the efficient dehydrogenative coupling of phenylphosphine oxides with alkynes, resulting in the synthesis of benzophosphole oxide derivatives 204 (Scheme 76).⁹⁷ Initially, they identified AgOAc as the optimized oxidant for this reaction. However, better results were achieved by employing Mn(OAc)₃ as the oxidant in certain cases. Building upon this work, Montchamp optimized the reaction conditions by introducing their established Mn(II) + Mn(IV) combination into the reaction system.^89b

Scheme 76 Synthesis of benzophosphole oxide derivatives. Miura et al. (2013);⁹⁷ Montchamp et al. (2019).^89b

In 2014, Zou and Zhang reported a diphenylphosphinoyl radical-initiated approach for the synthesis of 2-phosphinoylated 3,4-dihydronaphathalenes 206 from 1,4-diaryl-1-butynes 205 (Scheme 77).^98a The reaction stems from their previous successful work involving 1,4-diaryl-1-butenes.^98b Interestingly, the authors discovered that neither electronic nor steric effects exerted a significant influence on the product yield. Moreover, this reaction was further proved to enable the synthesis of phosphinoylated indene, benzo[7]annulene, and other related heterocyclic compounds. Later, the Li group developed a Mn(OAc)₃-promoted tandem phosphinoylation–cyclization of functionalized alkenes with disubstituted phosphine oxides (Scheme 78).⁹⁹ 2-Arylindoles and 2-arylbenzimidazoles 207 serve as the starting materials, leading to the formation of phosphoryl-substituted indolo[2,1-a]isoquinolin-6(5H)ones and benzimidazo[2,1-a]isoquinolin-6(5H)-ones 208 in up to 95% yield.

Scheme 77 Synthesis of 2-phosphinoylated 3,4-dihydronaphathalenes. Zou, Zhang et al. (2014).^98a

Scheme 78 Synthesis of phosphoryl-substituted indolo[2,1-a]isoquinolin-6(5H)one derivatives. Li et al. (2020).⁹⁹

In 2015, Tang and colleagues developed a Mn(OAc)₃ promoted radical oxidative phosphonation–lactonization of both terminal and internal alkenoic acids, enabling the synthesis of γ- and δ-lactone phosphonates 210 and 211via exo-selective or endo-selective cyclization processes (Scheme 79).^100a Additionally, the authors demonstrated the phosphonation–annulation of hydroxyalkenes and P(O)–H compounds in a similar manner, resulting in the formation of β-phosphonotetrahydrofurans and β-phosphonotetrahydropyrans. Notably, this reaction also proceeds successfully with a Cu(II) catalyst and stoichiometric amount of TBHP.^100b

Scheme 79 Synthesis of γ- and δ-lactone phosphonates. Tang et al. (2015).^100a

In 2019, Vincent et al. described the Mn(OAc)₃-promoted dearomative addition of phosphonyl radicals to indoles (Scheme 80).^101a This reaction resulted in the diastereoselective synthesis of α-amino phosphonate derivatives 213 embedded in a spirocyclic indoline framework. The reaction mechanism involves the addition of the phosphonyl radical to the C2 position of the indole, followed by oxidation of the resulting radical to a carbocation. Subsequently, a trans-fashion interception of the resulting carbocation by an O-nucleophile followed by rearomatization of the indole afforded the desired products Later, Ji's group reported a Mn(OAc)₃-promoted radical addition–[4 + 1] cyclization relay reaction between 3-indolymethanols and phosphites, yielding 1,2-oxaphospholoindole derivatives 214. Extensive mechanistic investigations and DFT calculations revealed that the reaction proceeded through a cascade of radical addition and intramolecular cyclization.^101b

Scheme 80 Intramolecular phosphonation–cyclization of substituted indoles. Vincent et al. (2019);^101a Ji et al. (2021).^101b

Phosphorus radical cyclization with isocyanide under Mn(III) promoted or catalyzed conditions is another well-explored type of reaction. This strategy enables the construction of heteroarenes containing a P(O)R₂ functionality, which are normally hard to prepare using other methods. In 2014, Zhao and Wu independently demonstrated the synthesis of 6-phenanthridinephosphonates using 2-isocyanobiphenyl as the starting material. These reactions share a similar mechanism to that revealed by Chatani's pioneering work in 2012,³⁹ albeit using H-phosphonates or diphenylphosphine oxides as radical precursors instead of organoboronic acids (Scheme 81).^102a,b This type of reaction was later optimized as a catalytic version using Mn(OAc)₂ and a ligand under electrooxidative conditions,^102c Subsequently, Li, Wen and co-workers realized the synthesis of the same 6-phenanthridinephosphonate products from 2-biaryl isothiocyanates via a tandem phosphorylation/cyclization process, accompanied by the elimination of H₂S. In this reaction, the Mn catalyst functions as a Lewis acid rather than as an oxidant.^102d Very recently, Yao, Qin et al. developed a Mn(acac)₃ catalyzed synthesis of 4-CF₃-2-phosphinoylquinolines via radical 6-endo–trig cyclization. Control experiments excluded oxygen as the external oxidant for the reaction. The proposed mechanism involves an alkyl Mn(III) intermediate, which undergoes β-hydride elimination to afford the desired product. Protonation of the Mn(III) hydride species regenerates the Mn(III) catalyst.^102e

Scheme 81 Mn(III) promoted radical phosphonation with isocyanide.

In summary, significant advancements have been made in Mn(III)-promoted phosphonation over the past decade, particularly in the cyclization processes that produce novel phosphonated heterocycles and the dual functionalization of alkenes. However, there are notable drawbacks in this field. One major limitation is the narrow scope of reactions. For instance, only a few phosphinylidene substrates are currently utilized in the construction of C–P bonds promoted by Mn(III), which restricts the broader applicability of this method in practical synthesis. Another consideration is that the low toxicity of manganese is advantageous for expanding these reactions to bioorthogonal synthesis. Nevertheless, advancing this area will require reducing the amount of Mn(III) used and carefully designing the reaction reagents. Despite these challenges, the potential for growth in this field is substantial, and it is certain that more prosperous developments will be witnessed in the near future.

6. C–N bond formation

C–N bond formation promoted by Mn(OAc)₃ is relatively uncommon compared to the construction of C–C, C–O, and C–P bonds. However, there have been notable studies on the formation of C–N bonds through the SET between Mn³⁺ and azide (N₃⁻). The pioneering work by Fristad et al. in 1985 demonstrated the conversion of alkenes to 1,2-diazides in the presence of Mn(OAc)₃ and NaN₃.^103a These diazide products can be easily transformed into 1,2-diamines, which are valuable scaffolds in medicinal chemistry. The proposed mechanism for this reaction involves either ligand transfer oxidation via the Mn(III)–N₃ complex or simple addition of the free N₃ radical to the alkene. This straightforward method has also been successfully employed in the synthesis of alkyl azides from unsaturated fatty compounds.^103b

In 2014, Wang et al. conducted a study on the Mn(III)/TEMPO co-mediated azidation–1,2-carbon migration cascade reaction of allylic silyl ethers 223 (Scheme 82).¹⁰⁴ This reaction led to the preparation of a variety of β-azido ketones 224 with an α-quaternary stereocenter in up to 95% yield. Interestingly, when dihydropyran-type allylic silyl ethers were used as substrates, the dominant product obtained was the diazide addition product. Furthermore, this diazide product could also be converted into the desired β-azido ketones via a BF₃-promoted deazidation–1,2-carbon migration process.

Scheme 82 Synthesis of β-azido ketones. Wang et al. (2014).¹⁰⁴

Mn(III) promoted radical cyclization cascades with azides are employed to construct numerous potent bioactive heterocyclic azides based on exquisite substrate designs.¹⁰⁵ In 2016, Wan, Li, and coworkers developed a catalyst-controlled diastereodivergent azidation–cyclization of 1,7-enynes 225 (Scheme 83).¹⁰⁶ The Mn(OAc)₃-catalyzed reaction resulted in the formation of trans-fused pyrrolo[3,4-c]quinolinones 226 with good diastereomeric ratios, while reactions catalyzed by Cu(II) exclusively produced cis-products. The authors tentatively proposed that the diastereodivergence resulted from Mn coordination with the nitrogen atoms of the substrates, followed by azide transfer. In contrast, pronounced steric repulsion in the Cu(II)/bipyridine system facilitated azide attack on the opposite side, leading to the formation of cis-products.

Scheme 83 Synthesis of trans-fused pyrrolo[3,4-c]quinolinones. Wan, Li et al. (2016).¹⁰⁶

In 2017, Hao, Chen, and coworkers achieved the Mn(OAc)₃-mediated oxidative carboazidation of acrylamides, successfully synthesizing a variety of azido oxindoles 229 in up to 99% yield (Scheme 84).¹⁰⁷ The authors also demonstrated a catalytic procedure using TBPB as the terminal oxidant, albeit with slightly lower efficiency compared to Mn(OAc)₃-mediated reactions. The reaction proceeds through a cascade of radical addition, cyclization, and subsequent oxidation steps, ultimately yielding the desired product. Notably, under the Mn(OAc)₃/TBPB conditions, a pathway involving a Mn(II)/Mn(IV)/Mn(III) cycle is proposed.

Scheme 84 Synthesis of azido oxindoles. Hao, Chen et al. (2017).¹⁰⁷

Chandrasekhar and co-authors conducted a study on the Mn(OAc)₃-catalyzed azide radical addition/cyclization/oxygen insertion cascade with TMSN₃ under mild conditions (Scheme 85).¹⁰⁸ The authors investigated the reactions of various alkyne-tethered cyclohexadienones 230, leading to the formation of cis-fused bicyclic azido alcohols 231 with good diastereoselectivity and yields ranging from 35% to 80%. Furthermore, the obtained azido alcohol products can be readily transformed into 1,2,3-triazoles through a Cu-catalyzed click reaction.

Scheme 85 Synthesis of cis-fused bicyclic azido alcohols. Chandrasekhar et al. (2020).¹⁰⁸

As an alternative to Mn(OAc)₃, MnBr₂ has been used to achieve C–N bond formation with azides through a Mn(II)/Mn(III) catalytic cycle. For instance, the Jiao group reported a MnBr₂-catalyzed aerobic oxidative hydroxyazidation of olefins using TMSN₃ (Scheme 86).^109a Although Mn(OAc)₃ and Mn(OAc)₂ are effective catalysts for promoting the reaction, MnBr₂ has been identified as the ideal catalyst. Typically, a mixture of β-azido hydroperoxides and β-azido alcohols is obtained, requiring workup with PPh₃ to obtain pure β-azido alcohol products. Li et al. disclosed a modified procedure that utilized TBHP as both the substrate and terminal oxidant, leading to the major production of inherently unstable hydroperoxides.^109b In 2017, the Lin group reported a MnBr₂-catalyzed diazidation of alkenes under electrochemical conditions.^109c This reaction follows a similar mechanistic pattern to that reported in Fristad's study.^103a However, the successful establishment of a Mn(II)/Mn(III) cycle using anode oxidation has expanded the applicability of Mn(III) in both modern synthetic chemistry and pharmaceutical research. In a similar manner, Sarkar and coworkers showcased a MnBr₂-catalyzed electrochemical tandem azidation–coarctate reaction for the preparation of 2-azo-benzonitriles from 2H-indazole and sodium azide.^109d Later, the same group realized a MnBr₂-catalyzed electro-oxidative azidation–cyclization cascade, leading to the formation of oxindoles and quinolinones.^109e

Scheme 86 MnBr₂-catalyzed hydroxyazidation or diazidation of alkenes.

The presence of free amine typically deactivates Mn(OAc)₃, thereby inhibiting the initiation of other N radical precursors by Mn(III).¹¹⁰ Consequently, the formation of C–N bonds with other nitrogen sources commonly does not involve a nitrogen radical and instead relies on the catalytic properties of Mn(III) as a transition-metal catalyst or Lewis acid. In 2018, Chauvin, Cui, and colleagues reported a Mn(III)-catalyzed three-component cascade C–H/N–H functionalization of 2-aminopyridines 236 and dialkyl butyndioates 237 in one pot (Scheme 87).¹¹¹ This reaction resulted in the synthesis of numerous novel heterocycles 238 featuring an azacycl[3.2.2]azine core structure. The reaction employed a Mn(III) catalyst, bipy ligand, and DTBP as the terminal oxidant. Mechanistic studies revealed that the alkenyl manganese species, formed via the Michael addition of Mn(III) to diethyl acetylenedicarboxylates, underwent consecutive isomerization and insertion steps, ultimately leading to a tricyclic complex intermediate. Aromatization-driven deprotonation of the intermediate then gave rise to the formation of a capto-dative aminocarbene complex. Subsequently, intramolecular nucleophilic addition of the enamino group to the ester C–O bond occurred, resulting in the desired product. Nitrogen atoms played a dual role in these reactions, not only participating in C–N bond formation, but also serving as directing groups (Scheme 88).

Scheme 87 Synthesis of azacycl[3.2.2]azine derivatives. Cui et al. (2018).¹¹¹

Scheme 88 Proposed mechanism for Mn(III)-catalyzed cascade C–H/N–H functionalization of 2-aminopyridines. Cui et al. (2018).¹¹¹

Quinoline and isoquinolin-1(2H)-one frameworks serve as crucial building blocks with significant bioactivities and promising potential. In 2019, Niu, Song, and colleagues reported the intramolecular transformation of alkyne-tethered N-alkoxyamides 239 using the Mn(acac)₂/O₂ oxidation system (Scheme 89).¹¹² This methodology enabled the synthesis of 38 examples of substituted polycyclic isoquinolin-1(2H)-ones 240 with yields ranging from 30% to 96%. Mechanistic investigations revealed the formation of an organomanganese(III) intermediate, in which Mn(III) coordinated to the alkyne moiety. This was followed by a cascade of C–N bond formation, homolysis of the C–Mn bond, and aromatic homolytic substitution, affording the desired products.

Scheme 89 Synthesis of isoquinolin-1(2H)-ones. Niu, Song et al. (2019).¹¹²

In 2020, Zhang et al. demonstrated a selective C–C bond cleavage and annulation strategy using 2-styrylanilines 241 and β-keto esters as starting materials (Scheme 90).¹¹³ The synthesis of quinoline-2-carboxylates 242 was achieved when Mn(OAc)₃ was employed as the promoter; instead, 2-alkylquinolines were prepared when I₂ was used. The authors proposed tentative mechanisms to elucidate the promoter-dependent selectivity. The key step involved the initial formation of a β-enamino ester intermediate under I₂ conditions, whereas the presence of Mn(OAc)₃ led to the generation of a carbon-centered radical 243 through free radical addition of the α-carbonyl radical to 2-styrylaniline. Subsequently, a series of processes, including H-migration, cyclization, oxidative deacylation and dehydrogenation, occurred, resulting in the production of the desired products.

Scheme 90 Synthesis of quinoline-2-carboxylates. Zhang et al. (2020).¹¹³

In 2017, Dong, Zhou and coworkers developed a Mn(OAc)₃-catalyzed oxidative amination of benzylic C(sp³)–H bonds using nitrile substrates. The reaction enabled the synthesis of a diverse array of functionalized secondary amides 246 in up to 96% yield (Scheme 91).¹¹⁴ Interestingly, while DDQ alone could promote the reaction, the authors discovered that the interaction between Mn(III) and DDQ played a crucial role in enhancing both the efficiency and selectivity of the reaction. Kinetic isotope effect (KIE) experiments suggested that the cleavage of the C–H bond might be the rate-limiting step in this transformation.

Scheme 91 Synthesis of secondary amides. Dong, Zhou et al. (2017).¹¹⁴

7. C–S bond formation

In a manner analogous to C–P and C–N formation described above, Mn(OAc)₃ can facilitate the generation of sulfur radicals through a one-electron oxidation process, ultimately facilitating the formation of C–S bonds. Previous studies demonstrated the effective utilization of aromatic thiols or ammonium thiocyanate (NH₄SCN) as sulfur radical precursors.¹¹⁵

Zhang et al. presented a novel approach for the synthesis of naphtho[2,1-d]thiazoles 248 through an intramolecular cyclization of 3-(2-naphthyl)-1-substituted acylthiourea 247 in the presence of Mn(OAc)₃ (Scheme 92).¹¹⁶ The reaction commences with the isomerization of the thiocarbonyl group to a thioenol, which undergoes oxidation by Mn(III) to generate sulfur radicals. Subsequently, radical cyclization occurs, followed by further oxidation to yield the desired product.

Scheme 92 Synthesis of naphtho[2,1-d]thiazoles. Zhang et al. (2020).¹¹⁶

Sulfinate salts (RSO₂M) have attracted significant attention for their versatile reactivity and have emerged as valuable building blocks for the synthesis of sulfonyl-group-containing molecules.^117a Mn(OAc)₃ is demonstrated to serve as an effective catalyst to facilitate the one-electron oxidation of sulfinate salts, leading to the formation of sulfonyl radicals.^117b These sulfonyl radicals can then participate in various transformations to construct sulfone compounds.^117c Manolikakes et al. reported a series of C–H bond sulfonylation reactions using sulfinate salts, promoted by Mn(OAc)₃. Among them, the remote sulfonylation of 8-aminoquinolines^118a or aniline derivatives^118b required a copper catalyst, possibly in the form of anionic imide copper(II) complexes, to facilitate the intermolecular SET process (Scheme 93). However, the oxidative sulfonation of 1,4-dimethylbenzene proceeded efficiently without the need for a copper catalyst (Scheme 94).^118c To enhance the synthetic utility of their method, the authors explored oxidative sulfonylation using lithium sulfinate, which could be readily prepared through the reaction of the corresponding organolithium compounds with sulfur dioxide.

Scheme 93 Sulfonylation of 8-aminoquinolines and aniline derivatives. Manolikakes et al. (2016) & (2017).^118a,b

Scheme 94 Sulfonation of 1,4-dimethylbenzene. Manolikakes et al. (2017).^118c

In a subsequent study, Manolikakes et al. developed a Mn(OAc)₃-promoted oxidative sulfonylation of enamides and encarbamates with sodium or lithium sulfinates (Scheme 95).^119a This approach enabled the preparation of a series of β-amidovinyl sulfones 254 with excellent E-selectivity in up to 98% yield. Later, the Terent'ev group achieved the synthesis of N-unsubstituted enaminosulfones 256 through the sulfonylation of vinyl azides 255 using sodium sulfinates.^119b Notably, the authors suggested that the generated iminyl radical could participate in the sulfinate oxidation step, which explained the use of substoichiometric amounts of Mn(OAc)₃ in the reaction.

Scheme 95 Synthesis of β-amidovinyl sulfone. Manolikakes et al. (2019);^119a Terent'ev et al. (2021).^119b

In 2016, Chen and co-workers reported efficient Mn(OAc)₃ mediated coupling reactions of sodium sulfite with nitro-olefins, resulting in the formation of (E)-vinyl sulfones 258 (Scheme 96).^120a It was observed that nitro-olefins containing electron-donating groups exhibited higher reactivity compared to those with electron-withdrawing groups, while the electronic properties of sulfinates did not exert a significant influence. In a similar manner, the Lu group realized the decarboxylated hydroxysulfonylation of arylpropiolic acid.^120b Water was employed as both the solvent and reactant, facilitating the generation of diverse β-ketosulfones 260. The key aspect of these two transformations lies in the selective addition of sulfonyl radicals to double or triple bonds.

Scheme 96 Synthesis of (E)-vinyl sulfones and β-ketosulfones. Chen et al. (2016);^120a Lu et al. (2018).^120b

Recently, Xia, Song, and Guo successfully employed Mn(acac)₃ as a catalyst to facilitate the trifluoromethylsulfonylation reaction of diazo compounds 261 under visible light irradiation (Scheme 97).¹²¹ This reaction yielded α-trifluoromethyl sulfone esters 262 in up to 82% yield. The significance of this synthetic approach lies in its ability to selectively generate trifluoromethyl sulfonyl (CF₃SO₂) radicals, a relatively uncommon species, instead of the more common trifluoromethyl (CF₃) radicals. To gain a deeper understanding of the reaction mechanism, the researchers conducted DFT calculations, which provided compelling evidence supporting the proposed transformation pathway involving the formation of a stable manganese trifluoromethylsulfonyl intermediate 263.

Scheme 97 Synthesis of α-trifluoromethyl sulfone esters. Xia et al. (2023).¹²¹

Cyclization reactions can be achieved for the synthesis of heterocyclic sulfones utilizing in situ generated sulfonyl radicals. In 2016, Chuang's group successfully developed the Mn(OAc)₃-mediated sulfonylation of 2-(2-alkylphenyl) aminomaleates 264 with aryl sulfinates (Scheme 98).¹²² This method enabled the preparation of a series of 4-arylsulfonylmethyl-substituted quinolines 265 through a cascade of radical sulfonylation, 6-endo–trig cyclization, and subsequent aromatization. Interestingly, it was found that KMnO₄ could serve as an alternative to Mn(OAc)₃ in certain cases. The authors also demonstrated the sequential one-pot, two-step synthesis of 265 directly from (2-ethynylphenyl)amine 266.

Scheme 98 Synthesis of 4-arylsulfonylmethyl-substituted quinolines. Chuang et al. (2016).¹²²

In 2019, Liu et al. reported the development of a Mn(OAc)₃-promoted radical ipso cyclization between biaryl ynones 267 and sodium sulfinates, leading to the formation of sulfonated spiro[5.5]trienones 268 (Scheme 99).¹²³ This reaction proceeds via the simultaneous construction of C–S and C–C bonds, as well as the cleavage of a C–O bond, all in a single step. Notably, the authors observed that the selectivity of cyclization was somewhat influenced by electronic effects on the methoxybenzene ring, and ortho cyclization could yield a seven-membered benzoannulenone product.

Scheme 99 Synthesis of sulfonated spiro[5.5]trienones. Liu et al. (2019).¹²³

Reddy and co-workers recently reported an unexpected cycloannulative sulfonyl migration (Scheme 100).¹²⁴ This reaction unfolds through a sequential, one-pot method via oxa-Michael addition–elimination of (E)-β-iodovinyl sulfones and ortho-alkynylphenols. Subsequently, it undergoes cycloisomerization and sulfonyl migration in the presence of Mn(OAc)₃. Various vinyl sulfone-derived chromenes 270, including an estrone-derived analogue, were prepared in up to 75% yield with excellent stereoselectivities. The authors suggest that the key step in the cycloannulative sulfonyl migration is likely the formation of a Mn(III)–enyne complex 271, followed by thermal homolytic cleavage of the C–S bond, which would generate a liberated sulfonyl radical (Scheme 101).

Scheme 100 Synthesis of vinyl sulfone-derived chromenes. Reddy et al. (2023).¹²⁴

Scheme 101 Proposed mechanism for cycloannulative sulfonyl migration. Reddy et al. (2023).¹²⁴

Sulfonates and sulfonic acids play a crucial role as building blocks in enhancing the water solubility and polarity of molecules. They also serve as important precursors for synthesizing a wide range of derivatives containing sulfonyl groups. In 2022, Liang et al. reported a novel radical homolytic aromatic sulfonation method that was promoted by Mn(OAc)₃ and utilized K₂S₂O₅ as a mild sulfonating agent (Scheme 102).¹²⁵ This approach efficiently transforms a variety of aromatics, including unbiased arenes, substituted naphthylamines/naphthols, and electron-rich five-membered heterocycles, into the corresponding sulfonic acids or sulfonates. Notably, after extensive investigation of various one-electron oxidants, Mn(OAc)₃ emerged as the only effective oxidant for this sulfonation process. Mechanistic studies indicated that the SO₃⁻ radical acted as a sulfonic synthon, while the unique solvent effect of HFIP was found to be crucial for the success of the sulfonation reaction.

Scheme 102 Synthesis of (hetero)aryl sulfonates. Liang et al. (2022).¹²⁵

Shortly thereafter, the same group reported a Mn(OAc)₃ promoted radical sulfonation–cyclization cascade involving functionalized alkenes via the SO₃⁻ radical (Scheme 103).¹²⁶ This strategy enabled the one-step construction of oxindoles, quinolones, isoquinoline-1,3-diones, and benzoxazine-based sulfonates.^126a Furthermore, the approach was successfully extended to the sulfonation–ipso cyclization cascade of functionalized alkenes and alkynes, leading to the synthesis of azaspiro[4,5]-trienone-based sulfonate and azaspiro[4,5]-decane-based sulfonate compounds in good to excellent yields.^126b The authors also demonstrated a modular approach for synthesizing complex sulfonamide and sulfonate esters; these are typically challenging to prepare using conventional methods. This provides an opportunity to facilitate the late-stage functionalization of such compounds.

Scheme 103 Synthesis of heterocyclic sulfonates. Liang et al. (2022) & (2023).^126a,b

Other chalcogen-containing organic compounds like organoseleniums and organotelluriums demonstrate distinctive properties. In 2022, Lei's group developed an electrochemical Mn(III)-promoted selenylation reaction between boronic acids and diselenide (Scheme 104).^127a A diverse range of valuable unsymmetric selenoethers 275 were prepared in up to 99% yield. Through cyclic voltammetry (CV) and control experiments, it was revealed that under electrochemical conditions, the diselenide compound, rather than the arylboronic acid, underwent the initial oxidation, thereby facilitating the desired selenylation reaction. In the same year, Xu and Tan reported a Mn(OAc)₃-promoted reaction between isocyanide and ditelluride, leading to the formation of various N-acyl tellurocarbamates 277.^127b The generation of radical intermediate 278via the reaction of telluride radicals with isocyanides was proposed as the key step. These developments highlight the potential of Mn(OAc)₃ in enabling efficient and selective transformations for the synthesis of valuable organoselenium and tellurium compounds, further expanding the toolkit available to synthetic chemists.

Scheme 104 Synthesis of selenoethers and N-acyl tellurocarbamates. Lei et al. (2022);^127a Xu, Tan et al. (2022).^127b

In light of the aforementioned considerations, research on Mn(OAc)₃-promoted C–N and C–S coupling reactions remains relatively preliminary, highlighting the need for further in-depth investigations. It is essential to explore the direct application of amine compounds and a broader range of sulfur sources, even though these methods often lead to deactivation of the Mn(III) catalyst. To achieve these objectives, a deeper understanding of the oxidative capabilities of Mn(OAc)₃ is necessary. In this context, electrochemical methods present promising advantages, as they can effectively record and analyze the redox behavior of the Mn(II)/Mn(III) catalytic cycle.

8. Miscellaneous reactions

Apart from the ability to act as a mild one-electron oxidant for the construction of diverse C–C and C–heteroatom bonds, Mn(OAc)₃ proves to be an efficient oxidant for the direct oxidation of various reductive functional groups. In 2014, Mukherjee and Dey investigated the Mn(OAc)₃ catalyzed oxidation of substituted dioxolene and phenols. The reaction resulted in the formation of 3,5-di-tert-butylbenzoquinone (DTBQ) and 2-aminophenoxazinone (APX) with high efficiency. Mechanistic studies reveal the formation of a Mn(IV) intermediate without the involvement of any radical intermediate.^128a Furthermore, Mn(OAc)₃ was identified to be crucial for promoting the oxidation of secondary amines to imines, enabling the selective functionalization of [60]fullerenes.^128b,c In another study, Johnson et al. discovered that Mn(OAc)₃ and related Mn(III) complexes, such as Mn(acac)₃, were effective activators of galactose oxidase for biocatalytic alcohol oxidations. This makes the Mn(III) catalyst a convenient and economical replacement for expensive horseradish peroxidase.^128d In 2021, Yang and Niu reported a Mn(OAc)₃ catalyzed aerobic dehydrogenation of N-heterocycles, including indolines and tetrahydroquinolines (Scheme 105).^128e The reaction is believed to be initiated through SET from nitrogen to Mn³⁺, resulting in the formation of an aminium radical cation intermediate. This intermediate then reacts with O₂˙⁻, followed by coupling with a peroxide radical, reduction or homolysis, and the elimination of H₂O, ultimately yielding the desired products.

Scheme 105 Aerobic dehydrogenation of tertiary indolines. Yang, Niu et al. (2021).^128e

As mentioned previously, the use of excess amounts of Mn(III) salts can reduce the atom economy of the reaction and lead to cumbersome workup processes. While catalytic versions have been developed by various research groups, they typically require more than 5 mmol% Mn(III) to achieve synthetically meaningful yields. It is important to highlight that Mn(OAc)₂ in combination with an extra oxidant, such as O₂ or peroxides, is demonstrated to efficiently and selectively oxidize alcohols, sulfides, hydrocarbons, tertiary amines and isochroman to their corresponding oxidized products.^129a,b In 2018, Montilla, Galindo, and co-workers conducted a study on the Mn(OAc)₂ catalyzed aerobic oxidation of β-carbonylenehydrazines 281 for the synthesis of α,β-dicarbonylhydrazones 282 (Scheme 106).^129c The reaction involves a hydrogen-atom-transfer (HAT) process, which is promoted by in situ generated Mn(III)OH species. The authors found that a low catalyst loading of 0.025 mmol% Mn(OAc)₂ was sufficient to promote the reaction. Considering the lower cost of Mn(OAc)₂, these procedures using Mn(OAc)₂ as a catalyst may be more practical and suitable for applications in industrial production.

Scheme 106 Synthesis of α,β-dicarbonylhydrazones. Galindo et al. (2018).^129c

Olivo investigated the oxidation of 1-hydroxy-2-naphthalene carboxylates in the presence of Mn(OAc)₃ (Scheme 107).¹³⁰ The reaction appeared to be dependent on both the substrate and the conditions used. When benzene was employed as the solvent, the reaction favored the dimerization of the hydroxynaphthalene carboxylate, similar to the oxidative homocoupling of hydroxyanthracenone previously reported by Snider. In contrast, when using a mixture of AcOH and MeCN as the solvent, the products varied between acetoxylated compounds or quinones, depending on the substituents on the naphthol ring.

Scheme 107 Mn(OAc)₃ promoted oxidation of methyl 1-hydroxy-2-naphthalene carboxylates. Olivo et al. (2017).¹³⁰

With its mild conditions and exceptional selectivity, the utilization of Mn(OAc)₃ as a one-electron oxidant in radical cyclization reactions has found widespread acceptance as an ideal method for constructing C–C bonds in the total synthesis of various bioactive natural products. For instance, in the total synthesis of (−)-glaucocalyxin A 285 developed by Jia et al., the crucial 14-oxygenated bicyclo[3.2.1]octane compound 284 can be synthesized through a Mn(OAc)₃-mediated radical cyclization, involving intramolecular radical addition to an alkyne moiety (Scheme 108).^131a Later, the same group reported an elegant total synthesis of (+)-aberrarone 288, which featured a Mn(OAc)₃ promoted polyene cyclization. The key intermediate 287, containing a triquinane structure, was prepared through a Mn(OAc)₃-mediated intramolecular 5-exo/5-exo/5-exo radical cascade reaction of enyne 286.^131b In the short synthesis of aphanamol I 291, Burton et al. discovered that exposing dienyl malonate to oxidative radical cyclization conditions using Mn(OAc)₃ and Cu(OTf)₂ in acetonitrile led to the preparation of the key intermediate [3.3.0]-bicyclic γ-lactone 290 in excellent yield.^131c In a very recent study on the total synthesis of DMOA-derived spiromeroterpenoids, Porco et al. observed that the oxidative dimerization of DMOA methyl ester 292 was effectively promoted by the Mn(III)/Cu(II) system, resulting in the production of a complex dimer 293.^131d Furthermore, in 2015, Christensen and co-workers successfully applied the Mn(OAc)₃ mediated acetoxylation of enones in their semi-synthesis of 2-acetoxytrilobolide 296 and thapsigargin 298 from nortrilobolide (Scheme 109).¹³²

Scheme 108 Selected applications of Mn(OAc)₃ in total synthesis.

Scheme 109 Synthesis of 2-acetoxytrilobolide and thapsigargin. Christensen et al. (2015).¹³²

These selected examples demonstrate the versatility and practicality of Mn(OAc)₃ methodologies in the synthesis of complex natural products. However, while the utilization of Mn(III)–enolate intermediates proves to be successful in forming C–C/C–O bonds in total syntheses, there is growing demand for the application of Mn(OAc)₃ in the synthesis of more complex molecules that contain diverse carbon–heteroatom bonds. The general mechanism of these types of reaction is well understood and will not be elaborated on here. For a more detailed discussion regarding the application of Mn(OAc)₃ in the synthesis of natural products, readers can refer to a recent review by Biçer and Yilmaz.¹³³

9. Conclusion and outlook

In conclusion, notable progress has been achieved in the realm of Mn(OAc)₃-promoted/catalyzed reactions over the past decade. These advancements include the formation of various C–C, C–O, C–P, C–N, and C–S bonds through a diverse array of reaction types, such as addition/substitution, dual functionalization, and cascade functionalization/cyclization. Despite these achievements, to fully harness the potential of Mn(OAc)₃ in organic synthesis, there is a continued need for the development of efficient and reliable methodologies.

Several areas necessitate further exploration. One area of concern is the investigation of more types of reaction to expand the synthesis possibilities. Currently, most reactions occur at the active sites of substrates (intermolecular couplings) or require ingenious substrate designs (intramolecular cyclizations). A critical direction for development is the synthesis of compounds that lack directing groups, which often exhibit significant loss of regioselectivity. More research is needed on reactions that start from unbiased C–H bonds through the combination of Mn(OAc)₃ with other transition metal catalysts. Another issue is the chemoselectivity problem associated with Mn(OAc)₃ reactions. Although Mn(OAc)₃ is a mild one-electron oxidant, its oxidation potential is higher than that of many common oxidation-sensitive functional groups. Therefore, it is essential to precisely adjust the oxidation window of related Mn(III) reactions through solvent environment modifications and/or the addition of suitable ligands. This approach can help prevent multi-functionalization or overoxidation of substrates, thereby expanding the scope of reactions and enhancing the functional group tolerance. Meanwhile, it is essential to investigate asymmetric synthesis utilizing Mn(OAc)₃. The incorporation of chiral ligands or additional chiral catalysts presents a viable approach, yet this field remains largely unexplored and poses significant challenges.

Moreover, current synthesis methods often require the use of large quantities of Mn(OAc)₃ and hazardous solvents, complicating their implementation in industrial reactions for fine chemical synthesis. Therefore, it is crucial to optimize existing methods, with a focus on developing more sustainable reaction conditions. This includes the regeneration of Mn(III) oxidants, the adoption of greener energy sources, and the employment of environmentally benign solvents. With the ongoing evolution of innovative synthesis technologies, such as photochemistry, electrochemistry, and flow chemistry, achieving these targets is promising but requires concerted efforts from the research community. Overall, these research fields will undoubtedly contribute to the refinement of Mn(OAc)₃-based methodologies and enhance their broader applicability in the domain of organic synthesis and medicinal chemistry.

Author contributions

Jian Wang and Yan Zhang: Investigation, writing – original draft. Ying Zhou, Xin Gu and Bingxu Han: Investigation. Xuelu Ding and Shuai Liang: Supervision, writing – review & editing. All authors agreed to their contributions and gave their approval for this publication.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Sichuan Science and Technology Program (2022NSFSC1252) and the Natural Science Foundation of Shandong Province (ZR2020QB010).

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Footnote

† These authors contributed equally to this work.

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