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The Mn(III)-mediated radical cyclization of various β-dicarbonyl compounds with thienyl-substituted alkenes provides an efficient, high yielding access towards thienyl-substituted dihydrofurans, e.g. (III), (V)/(VI) and (VIII).

Phosphoryl radicals, generated by oxidation of diethyl phosphate with Mn(III) acetate, react selectively at the 3-position to give products of biological interest.

(Mn(OAc)3) [993-02-2] C6H9MnO6 (MW 232.09) InChI = 1/3C2H4O2.Mn/c3*1-2(3)4;/h3*1H3,(H,3,4);/q;;;+3/p-3/f3C2H3O2.Mn/q3*-1;m InChIKey = AHSBSUVHXDIAEY-FGQZGJNPCC (Mn(OAc)32H2O) [19513-05-4] C6H13MnO8 (MW 268.13) InChI = 1/3C2H4O2.Mn.2H2O/c3*1-2(3)4;;;/h3*1H3,(H,3,4);;2*1H2/q;;;+3;;/p-3/f3C2H3O2.Mn.2H2O/q3*-1;m;; InChIKey = ONJSLAKTVIZUQS-WDZKTAJACF (one-electron oxidant used to oxidize acetic acid and β-dicarbonyl compounds to the corresponding radical and for α′-acetoxylation of enones) Physical Data: the commercially available dihydrate is cinnamon brown. The anhydrous form is dark brown. The crystal structure of the anhydrous form indicates an oxo-centered trimer with bridging acetates.2 Solubility: sol acetic acid, ethanol, and a variety of other organic solvents; disproportionates in water. Preparative Method: commercially available dihydrate is easily prepared by the reaction of manganese(II) acetate with potassium permanganate in acetic acid at reflux.1 The anhydrous form is prepared in acetic acid and acetic anhydride.1

This article provides a broad overview of oxidative radical methods for the formation of CC bonds using manganese(III) acetate, cerium(IV) ammonium nitrate, and various iron(III) salts. The article begins with a discussion of the various general mechanisms encountered in oxidative radical chemistry and then provides an overview of inter and intramolecular CC bond-forming reactions. The oxidative radical chemistry of β-dicarbonyl and related compounds forms a major part of the article. Comparison of the three metals is made whenever possible as well as highlighting reactions which are specific to, or higher yielding with, one particular metal. The discussed synthetic methodologies are illustrated with examples of complex molecule synthesis. Keywords: manganese acetate; ceric ammonium nitrate; CAN; iron; oxidative; radical; synthesis

Radical cyclizations of fluorinated 1,3-dicarbonyl compounds with dienes mediated by Mn(OAc)3 afforded 4,5-dihydrofurans containing difluoroacetyl, trifluoroacetyl, or heptafluorobutanoyl groups in good-to-excellent yields. Additionally, 2-(difluoromethyl)-4,5-dihydrofurans and a 4,7-dihydrooxepin derivative were obtained as unexpected products in the reaction of 4,4-difluoro-1-phenylbutane-1,3-dione with 1,3-diphenylbuta-1,3-diene. The radical cyclization of symmetrical dienes such as 2,3-dimethylbuta-1,3-diene and 1,4-diphenylbuta-1,3-diene with 1,3-diketones furnished the corresponding products in low yields. However, treatment of 1-phenylbuta-1,3-diene with 1,3-dicarbonyl compounds afforded 4,5-dihydrofurans containing fluoroacyl groups. The radical cyclizations with 3-methyl-1-phenylbuta-1,3-diene and 1,3-diphenylbuta-1,3-diene led to 4,5-dihydrofurans in good yields, since Me and Ph groups at C(3) of these dienes increase the stability of the radical intermediate.

The functionalized benzanthracenes are useful synthons which can be converted into derivatives such as (V) and (VIII) as well as polycyclic carbazoles like (X).

International audience; An easily reproducible protocol allowing inter- or intramolecular spirocyclization on beta-dicarbonyl structures is described. This methodology could afford a wide variety of spirocyclic pharmacophores. As examples, highly substituted spirobenzophenanthridin-6(5H)-ones and spirolactones were synthesized. These scaffolds could be used for the design of many compounds exhibiting biological activities.

Methyl substituted 1-(phenylsulfonyl)indolines undergo tandem oxidation of the indoline ring and a C-2 methyl group. If there is no alkyl substituent at the C-2 position, nuclear acetoxylation can occur to afford oxindoles.

Manganese(III) acetate mediated oxidative additions of the α-aryl α-nitro ketones 1 and 9 to simple alkenes forms the isoxazoline N-oxides 3 and 10 as the main products in 13–62% yield. Depending upon the structure of the unsaturated system used, the α-allylated α-nitro ketones 4, the tricyclic product 5 or the aromatised isoxazole 7 were also obtained. The oxidative addition of α-methyl α-nitro ketones 11 to hex-1-ene has been shown to yield the γ-acetoxylated α-nitro ketones 12. Based upon the influence of substituents in both the α-nitro ketone and the alkene, the outcome of the reaction mechanism is discussed. The oxidative addition of α-nitro amides 13 to hex-1-ene furnished the cyclic nitronates 14 together with the isoxazolines 15, which have been shown to be formed independently during the course of the reaction. Representative oxidative radical additions were performed using anodically in situ generated manganese(III) acetate from catalytical amounts of manganese(II) acetate. In these cases, yields as high, or even slightly higher, were obtained compared to those reactions employing 2 molar equiv. of the transition metal oxidant.

A new strategy has been developed to effect selective Mn(OAc) 3 -mediated oxidative cycloaddition reactions of 1-alken-3-ynes with β-dicarbonyl compounds. The three-step sequence involves (1) protection of the triple bond of the substrate with the -Co 2 (CO) 6 group, (2) Mn-promoted radical addition of the β-dicarbonyl compounds with the complexed enyne, and (3) oxidative demetalation. Mono-, di-, and tricycles, containing 2,3-dihydrofuran and tetrahydrofuran rings, are produced by exclusive attack on the uncomplexed C=C in moderate overall yields; formation of bi- and tricyclic derivatives occurs with excellent cis-stereoselectivity. Molecular mechanics calculations indicate that the cis ring fusion in these systems is thermodynamically favored. Reactions of the Co-complexed substrates proceed with Mn(III) promotion alone, whereas the free enynes require combined Mn(III)/Cu(II) mediation to produce furan derivatives, apparently reflecting the relative ease of oxidation of the respective intermediate radicals to carbocations. For the complexed substrates direct experimental proof for the formation of free carbocations along the reaction coordinate has been obtained by methanol trapping

The efficient generation of aryl radicals from arylboronic acids by manganese(III) acetate is described. In aromatic solvents, in situ generated aryl radicals afford the corresponding biaryls in very good yields. This method works selectively, and yields are better than those from similar, previously described methods. Arylboronic acids carrying sensitive functional groups also work efficiently.

Manganese(III) acetate-based radical cyclizations of various fluorinated 1,3-dicarbonyl compounds with alkenes produce 3-fluoroacylated 4,5-dihydrofurans of type (III), (VI), or (IX) and 2-acetyloxy-2-fluoroalkyl tetrahydrofurans of type (XI).

International audience; A new series of monoamidoxime derivatives was synthesized using manganese(III) acetate by microwave irradiation. Several amidoximes (27-31, 33, 38) showed valuable in vitro activities toward Leishmania donovani promastigotes, exhibiting IC(50) values between 5.21 and 7.89 mu M. In parallel, the cytotoxicity of these compounds was evaluated on murine J774A.1 cells, revealing the corresponding selectivity index (SI). Among the 13 tested compounds, 4 monoamidoximes (27-30) exhibited an SI more than 20 times better than pentamidine. Moreover, monoamidoxime 28 (4-[5-Benzyl-3-(4-fluorophenylsulfonyl)-5-methyl-4,5-dihydrofuran-2-yl]- N'-hydroxybenzimidamide) is 40 times more selective than pentamidine, and 1.6 times more than amphotericin B, used as reference drug compounds. (C) 2011 Elsevier Masson SAS. All rights reserved.

Radical reaction of [60]fullerene with phosphonates or phosphine oxide mediated by manganese(III) acetate dihydrate in chlorobenzene under three different conditions afforded three different types of phosphorylated fullerenes: singly bonded fullerene dimers 2, hydrophosphorylated fullerenes 3, and acetoxylated fullerene derivatives 4. In addition, interconversions among the three types of phosphorylated fullerene derivatives have also been investigated. A possible reaction mechanism was proposed to explain experimental results.

The reactions of some 1,3-dicarbonyl compounds with cycloheptatriene derivatives in the presence of Mn(OAc)(3) were examined. Cycloheptatriene forms mainly [2+3] and [6+3] dihydrofuran addition products derived from cycloheptatriene. However, the reaction of acetylacetone with cycloheptatriene substituted with an electron withdrawing group exclusively gave products derived from the norcaradiene structure. The formation mechanism of the products as well as the role of the substituent attached to cycloheptatriene is discussed.

International audience; We report a new and efficient method of conducting a one-pot double Buchwald-Hartwig coupling reaction on 2,3-dihydrofuran derivatives bearing two bromine atoms. This rapid and convenient synthesis allows us to access a great variety of original mixed dicoupled compounds. The strategy appears promising for combinatorial chemistry and pharmacomodulation studies.

Radical cyclizations of conjugated esters and amides with 3-oxopropanenitriles in presence of manganese(III) acetate produced ethyl 4-cyano-2,3-dihydrofuran-3-carboxylates and 4-cyano-2,3-dihydrofuran-3-carboxamides in good yields. The radical cyclizations of conjugated amides gave 2,3-dihydrofurans in better yields than that of conjugated esters. Moreover, the reactions of thienyl substituted amides and esters with 3-oxopropanenitriles afforded 2,3-dihydrofurans more efficiently than phenyl substituted ones.

Mn(III)-based oxidative free-radical cyclization of phenylmenthyl ester 1e afforded 90% of 13 with 86% de. Cyclization of 31b provided 56% of (+)-podocarpic acid precursor 32e with 82% de. The direction of de was opposite in these two cases. Oxidative cyclization of α-methyl β-keto ester 44b gave a 1:1.6 mixture of 46b and 47b while α-propyl β-keto ester and produced a >10:1 mature of46d and 47d indicating that the extent and direction of de is dependent on the size of the α-substituent. The reaction proceeds through transition states 12 and 56 with large α-substituents and through transition states 19 and 57 with small α-substituents. The de depends on the double-bond substitution pattern

Allylic cyclobutanols 1, 10, 21, 27, 32, 39, 51, and 58 are oxidatively fragmented by Mn(OAc) 3 -2H 2 O in EtOH to give tertiary radicals as shown in eq 1. These tertiary radicals undergo both 6-endo-cyclization to the α,β-unsaturated ketone to afford α-keto radicals and 5-exo-cyclization to provide β-keto cyclopentylmethyl radicals. The α-keto radicals produced by 6-endo-cyclization are reduced to ketones or dimerize. The β-keto radicals formed by 5-exo-cyclization are oxidized by Cu(OAc) 2 to yield methylenecyclopentanones and rearrange to give 3-oxocyclohexyl radicals that are oxidized by Cu(OAc) 2 to afford cyclohexenones. Acetylenic cyclobutanols 47, 49, and 65 are oxidatively fragmented by Mn(OAc) 3 .2H 2 O in EtOH to provide tertiary radicals that cyclize to give α-keto vinyl radicals, which abstract a hydrogen atom to yield methylenecyclopentanones. Pentenylcyclobutanol 75 is oxidatively fragmented by Mn(OAc) 3 .2H 2 O to afford tertiary radical 74, which cyclizes to furnish cyclopentylmethyl radicals 77 and 78, which are oxidized by Cu(OAc) 2 to methylenecyclopentanes 76 and 79

Reaction of β-ketoesters and β-dicarbonyl compounds with manganic acetate in acetic acid gives intermediates, which add to exocyclic enol ethers to afford a variety of interesting spirocyclic acetals. As the exocyclic enol ethers are shown to be readily accessible, the results constitute a useful route based on radical chemistry to the synthesis of unsaturated spiroacetals.

Reaction of manganic acetate in acetic acid with β-diketones and β-ketoesters leads to generation of intermediates, which add efficiently to endocyclic unsaturated enol ethers to afford fused acetals.

Imine radicals or enamine radicals generated by manganese acetate [Mn(OAc) 3 ] or copper acetate [Cu(OAc) 2 ] can be oxidized by the same metallic salts to produce α,β-unsaturated imines or α,β-unsaturated enones in good yields.

The oxidation of diethyl ω-phenylalkenylmalonates by Mn(III) acetate in acetic acid and Fe(III) perchlorate nonahydrate in acetonitrile or acetonitrile/acetic anhydride is investigated. Diethyl cinnamylmalonates 1 , 2 and 3 afford intramolecular addition products to the double bond (cyclopropanes 10 ) and to the aromatic ring (tetrahydronaphthalenes 8 or 9 ). A mechanism based on a fast and reversible 3- exo-trig -addition of malonyl radicals leading to cis-trans equilibration of the double bond, followed by competition between oxidation of benzyl radicals and intramolecular aromatic substitution, is suggested. Trapping experiments with styrene and metal ions elucidate some of the kinetic parameters involved. Similarly, compounds 4 and 5 are oxidized by Mn(III)/AcOH and FEP/AN to 4- and 5- exo-trig - cyclization products. In contrast, an outer-sphere electron-transfer mechanism is suggested in the oxidation of 1 , 4 and 5 at the styrenic double bond by FEP/AN-Ac 2 O and of benzalketones 6 and 7 by Mn(III)/AcOH to α-oxygenation products 21–22 .

Oxidation of diverse β-diketones and β-ketoesters with manganic acetate generates intermediates which add to exocyclic enol lactones to afford spirocyclic lactone products. In the presence of added copper acetate the reaction pathway can be diverted to give unsaturated ketoesters.

A thiyl radical cyclization approach to the sulphur containing ring of cephams is described. The reaction was carried out using metals able to perform a single-electron oxidation process under stoichiometric [Fe(III), MN(OAc) 3 ] or catalytic [Fe(III)] conditions. Furthermore, the FeCl 3 or Mn(OAc) 3 /LiX promoted reactions afforded, by a double single-electron oxidation process, over oxidized compounds. The relationship with the mechanistic hypothesis proposed by Baldwin for the DAOC/DACS-catalyzed ring expansion from Penicillin N to Desacetoxy cephalosporin C is discussed.

In the presence of malonic acid, the reaction of 1-acetylindole (2) with manganese(III) acetate resulted in the formation of 4-acetyl-3,3a,4,8b-tetrahydro-2H-furo[3,2-b]indol-2-one (5). The same reaction of 1-acetyl-2,3-dimethylindole yielded a mixture of 2-acetoxymethyl-1-acetyl-3-methylindole (7) and 4-acetyl-3a,8b-dimethyl-3,3a,4,8b-tetrahydro-2H-furo[3,2-b]indol-2-one (8), furthermore, the oxidation of 1-acetylindoline proceeded to the formation of 2, 5 and 1-acetylindoline-5-carboxylic acid (9)

Oxidative free-radical cyclization of 11a or 11b in the presence of Mn(III) and Cu(II) leads to the expected dienylcyclopentane 14 by rapid oxidation of the kinetically formed cyclopentanealkyl radical 13. Oxidative cyclization of 11a with Mn(III) only in ethanol or with benzoyl peroxide in cyclohexane affords a mixture of the stereoisomers of methylhydrindane 15. As expected, the first cyclization of the stabilized acyclic radical 12 is reversible. The second cyclization of the unstabilized cyclohexyl radical 17 leads to the hydrindanemethyl radical 16.

The α-oxidation of cyclic derivatives of α-alkoxy-α, β-unsaturated ketones using manganese(III) acetate in the presence of various carboxylic acids provided a convenient synthesis of 5-acyloxy-2-alkoxy-2-cyclopentenones and 6-acyloxy-2-alkoxy-2-cyclohexenones.

Treatment of various N-hydroxy-2-azetidinones with Mn(III) acetate unexpectedly afforded the corresponding reduced N-unsubstituted-2-azetidinones in the presence of hydrogen donor solvents.

Manganese(III) mediated reactions of unsaturated systems with carbonyl compounds are discussed in this review which focuses mainly on publications of the last decade. The process on the whole is highly selective both at the initiation and functionalization steps. Manganese(III) acetate generates α-oxo- and α,α-dioxoalkyl radicals by regioselective oxidation of carbonyl compounds, such as, aldehydes, ketones, acids, diketones, keto esters, and diesters. The functionalization step, which consists of the introduction of α-oxo- and α,α-dioxoalkyl moieties into multiple bond containing substrates, occurs in most cases with high regio-, chemo- and stereoselectivities

The reaction of lactonization of olefins with carboxyalkyl radicals and Mn(OAc) 3 was carried out under ultrasound irradiation at low temperatures. Good yields of lactones were obtained in short reaction times. In sonochemical conditions, reoxidation of Mn(II) occurred, allowing the development of a lactonization procedure with a catalytic amount of Mn(III).

The kinetics and mechanism of polymerisation of acrylamide initiated by manganese(III) acetate-citric acid (CA) redox system in aqueous acetic acid and sulphuric acid medium were studied over the temperature range 30-50° C. The overall rates of polymerisation (Rp), disappearance of manganic ion (—Rm), and degree of polymerisation (Xn) were measured with variation in [monomer], [Mn3+], [CA], [H+], μ and temperature. The polymerisation is initiated by the organic free radical arising from the Mn3+-CA reaction and the termination is by metal ions. The various rate parameters were evaluated and discussed.

Oxidative free-radical cyclization of α-chloromalonate 9 with Mn(OAc)3·2H2O and Cu(Oac)2·H2O in acetic acid at 75 °C provides 82% of lactones 10a and 10b. Hydroboration of 10 followed by oxidation affords acids 12, which are converted to avenaciolide precursor 15 in 32% overall yield from 9 by decarboxylation and cyclization.

The manganese(III) initiated oxidative free radical reaction between 2-hydroxy-1,4-naphthoquinone and β-enamino carbonyl compound 2 is described. Enamine radical 5 can be generated effectively from the oxidation of enamine 2 by manganese(III) acetate. Spirolactam 3 was prepared effectively from readily available 2-hydroxy-1,4-naphthoquinone and enamine 2 .

The chemistry of manganese based oxidants (permanganate, manganese dioxide, manganese(III) acetate and manganese(V) complexes) is reviewed. Possible mechanisms for the reactions between manganese based oxidants and organic compounds are described and the evidence, both experimental and theoretical, on which the proposed mechanisms are based is presented. Special emphasis is placed on identification of the structures of the transition states and reactive intermediates that are formed as these reactions proceed. Keywords: Oxidant; Permanganate; Manganese dioxide; Manganese(III) acetate; Manganese(V) salen; Manganese(V) porphyrin

The α-oxidation of aryl alkyl ketones using manganese(III) acetate in the presence of various carboxylic acids and (1S)-(+)-10-camphorsulfonic acid provided a convenient synthesis of α-acyloxy, α-(10-camphorsulfonyloxy), and α-hydroxy derivatives in good yield.

The reaction of methoxynaphthalenes with malonamide in the presence of magnanese(III) acetate gives 2-acetoxy-2-(1-naphthyl)propanediamides and 2-hydroxy-2-(1-naphthyl)propanediamides. It was found that the propanediamidation reaction did occur when naphthalenes have electron-donating substituents, such as a methoxyl group. The reactions of methoxynaphthalenes with ethyl 3-oxobutanoate, 2-cyanoacetamide, and malononitrile in the presence of manganese(III) acetate also yielded the corresponding substituted naphthalenes, ethyl 2-(acetoxymethyl)naphtho[2,1-b]furan-1-carboxylates, and/or a 4-methylene-1(4H)-naph-thalenone. The reaction mechanisms are discussed.

The α'-oxidation of cyclic derivatives of β-alkoxy-α,β-unsaturated ketones using manganese(III) acetate in the presence of various carboxylic acids provided a convenient synthesis of 5-acyloxy-3-alkoxy-2-cyclopentones and 6-acyloxy-3-alkoxy-2-cyclohexenones

Anodic oxidation in a solution containing a variety of olefins and a small amount of Mn(OAc)2·4H2O brought about Mn+3-mediated carbon—carbon bond formation, such as efficient carboxymethylation of styrene derivatives to the corresponding γ-aryl-γ-butyrolactones, and selective coupling of active methylene compounds with non-activated monoolefins, unconjugated dienes or 5-arylpent-1-enes.

The reactions of 1,1-diphenylethene, 1,1-bis(4-chlorophenyl)ethene, 1,1-bis(4-methoxyphenyl)ethene, 1,1-bis(4-methylphenyl)ethene, 1,1-bis(4-fluorophenyl)ethene, styrene, 1-octene, cyclohexene, and cyclooctene with tris(2,4-pentanedionato)manganese(III) ([Mn(acac)3]) in acetic acid at room temperature give 4-acetyl-3-methyl-1,2-dioxan-3-ol in 8–92% yields, together with 3-acetyl-4-hydroxy-3-hexene-2,5-dione. The similar reactions of 1,1-diphenylethene with 2,4-pentanedione, 3-methyl-2,4-pentanedione, 3-ethyl-2,4-pentanedione, 1-phenyl-1,3-butanedione, acetoacetanilide, and 1,3-cyclohexanedione in the presence of manganese(III) acetate also give the corresponding cyclic peroxide in good to moderate yields. The mechanisms of manganese(III)-induced 1,2-dioxane ring formation and concomitant radical side reaction are discussed.

The reactions of 1,1-disubstituted ethenes with acetoacetamide or N-substituted acetoacetamides, and molecular oxygen in the presence of manganese(III) acetate gave a mixture of c-4- and t-4-carbamoyl-3-methyl-1,2-dioxan-r-3-ols in good yields. Effects of substituents in the alkenes as well as in the carbamoyl group in the acetoacetamides were observed. Stereochemistry and the reactivity of the 4-carbamoyl-3-methyl-1,2-dioxan-3-ols are discussed.

The manganese(III) initiated oxidative free radical reaction between N-aroylindoles and dimethyl malonate giving indolo[2,3-a]isoquinolines is described.

In the presence of malonic acid, the reaction of 1-acetylindole (2) with manganese(III) acetate resulted in the formation of 4-acetyl-3,3a,4,8b-tetrahydro-2H-furo[3,2-b]indol-2-one (5). The same reaction of 1-acetyl-2,3-dimethylindole yielded a mixture of 2-acetoxymethyl-1-acetyl-3-methylindole (7) and 4-acetyl-3a,8b-dimethyl-3,3a,4,8b-tetrahydro-2H-furo[3,2-b]indol-2-one (8), furthermore, the oxidation of 1-acetylindoline proceeded to the formation of 2, 5 and 1-acetylindoline-5-carboxylic acid (9)

The manganese (III) initiated oxidative free radical reaction of electron rich 3-heteroaryl substituted malonates is described.