Heterocyclic Hydroperoxides in Selective Oxidations - Chemical

Chem. Rev. 2007, 107, 3338−3361

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Heterocyclic Hydroperoxides in Selective Oxidations Feyissa Gadissa Gelalcha* Leibniz Institut fu¨r Katalyse an der Universita¨t Rostock, e. V. Albert Einstein Str. 29a, D-18059 Rostock, Germany Received July 18, 2006

Contents

1. Introduction and Scope

1. Introduction and Scope 2. N-Heterocyclic Hydroperoxides 2.1. 4a-Hydroperoxy Flavins and Related Systems 2.1.1. General Properties and Synthesis 2.1.2. Mechanism of Activation of Dioxygen and Substrate Oxidation 2.1.3. Stoichiometric Oxidation of Sulfides and Amines 2.1.4. Catalytic Oxidation of Sulfides and Amines 2.1.5. Catalytic Asymmetric Oxidation of Sulfides 2.1.6. Role of 4a-Hydroperoxyalloxazins in the Os-Catalyzed Dihydroxylation of Alkenes 2.1.7. Aromatic Hydroxylation 2.1.8. Baeyer−Villiger Oxidation of Ketones 2.1.9. Oxidation of Aldehydes to Carboxylic Acids 2.1.10. Dioxygenase Activities of 4a-Hydroperoxy Flavins 2.2. R-Azo-hydroperoxides 2.3. Hydroperoxy Isoindolinones and Hydroperoxy Indolinones 2.4. Hydroperoxy Pyrrolidones 3. O-Heterocyclic Hydroperoxides 3.1. Sugar-Derived Hydroperoxides 3.2. Xanthene Hydroperoxides 3.2.1. Synthesis and Properties 3.2.2. Epoxidation of Alkenes 3.2.3. Oxidation of Sulfides, Sulfoxides, and Thiols 3.3. Dioxolane Hydroperoxides 4. N,S-Heterocyclic Hydroperoxides 4.1. Thiazolidine Hydroperoxides 4.2. Hydroperoxy Sultams 4.2.1. Synthesis 4.2.2. Oxidations with Hydroperoxy Sultams 5. Miscellaneous 5.1. R-Hydroperoxycamphorsulfonyl Amides 5.2. Hydroperoxy Selenuranes 6. Conclusions and Outlook 7. Acknowledgment 8. References

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* To whom correspondence should be addressed. Phone: +49(0)381 1217 953. E-mail: [email protected].

The chemo-, regio-, and stereoselective introduction of oxygen into organic molecules represents a key chemical transformation with wide-ranging significance both for the chemical industry and for biological processes. Although many efficient oxidants have been developed for specific reactions,1 molecular oxygen and hydrogen peroxide can be regarded as the best oxidants compatible with current environmental concerns. However, these oxidants are rarely used alone and frequently require heavy metal catalysis for further activation. Understanding the mechanism of oxygen transfer is the requisite for development of economically and ecologically feasible organic or inorganic oxidation catalysts. Organic hydroperoxides, which can be regarded as an ‘activated’ form of hydrogen peroxide, may also be used as complementary to these oxidants. In fact, tert-butylhydroperoxide and cumene hydroperoxide are among the most commonly used oxidants that have found viable application for large-scale organic oxidations. However, it is generally known that the oxidizing capacity of hydroperoxides can often increase dramatically if the peroxy function is linked close to electronegative groups, especially those in heterocyclic rings. Recent reviews compile organocatalytic selective oxidation systems with oxidants of various structures.2,3 However, heterocyclic hydroperoxides have been largely underrepresented, although some of these constitute the best choice for selective oxidations even in nature. It is the purpose of this review to highlight efforts made toward the realization of selective oxidations using heterocyclic hydroperoxides. By gathering data scattered in original research articles an attempt is made to provide the reader with a comprehensive and critical overview of synthetically relevant selective oxidation systems during the last decades that use various heterocyclic hydroperoxides. A common feature of most of the hydroperoxides discussed here is the presence of one or more electronegative groups in the ring close to the hydroperoxy function (mostly in the R position). This would activate the peroxy function for facile oxygen transfer by one or more of the following ways: (i) inductive polarization of the O-O bond, (ii) intramolecular hydrogen bonding, (iii) stabilization of the intermediate upon O-O bond cleavage. The heterocyclic structures permit oxygen (by using reducing equivalents) or H2O2 incorporation and may be regenerated after oxygen transfer, which opens a new world of organocatalysis for green oxidation chemistry. The extent of these effects, which are either absent or less favorable with ordinary organic alkylhydroperoxides that lack such groups, could vary with the specific hydroperoxide under consideration. Hydroperoxides in which the peroxy function is not directly attached to a heterocyclic ring structure, such as the furyl hydroperoxides4 and the TADDOH-derived hydroperoxides,5 are outside the scope of this review as are metallacycles.

10.1021/cr0505223 CCC: $65.00 © 2007 American Chemical Society Published on Web 07/11/2007

Heterocyclic Hydroperoxides in Selective Oxidations

Chemical Reviews, 2007, Vol. 107, No. 7 3339 Scheme 1

Scheme 2

Feyissa Gadissa Gelalcha was born in Oromia, Ethiopia. After winning a scholarship, he moved in 1988 to East Germany, where he studied chemistry at the former Technische Hochschule Leuna-Merseburg and at the Martin-Luther-Universita¨t Halle-Wittenberg and earned his Diploma (M.S.) in 1994 and his Ph.D. in 1998 in the area of asymmetric catalytic oxidations with Prof. Dr. Manfred Schulz. He did postdoctoral research with Prof. Dr. Waldemar Adam at the University of Wu¨rzburg, Germany, with Prof. Dr. Thomas R. Ward at the University of Berne, Switzerland, with a fellowship from the Swiss National Science Foundation (SNSF), and with Prof. Dr. Ba¨rbel Schulze at the University of Leipzig, Germany, all in the fields of oxidation chemistry and catalysis. Currently, he is research fellow at the Leibniz Institute for Catalysis in Rostock, Germany, with Prof. Dr. Matthias Beller. His research interests include the design and synthesis of sustainable oxidation catalysts, asymmetric catalysis, peroxide, and heterocyclic chemistry.

N-, O-, N,S-, and N,Se-Heterocyclic hydroperoxides as well as related systems where heterocyclic hydroperoxides are implicated as active oxidant species are presented in sections 2, 3, 4, and 5, respectively. Biomimetic oxidations with flavin hydroperoxides dominate section 2, followed by oxidations with R-azo-hydroperoxides, indolinone hydroperoxides, and N-alkylpyrrolidone hydroperoxides, in that order. In section 3 oxidations with sugar, xanthene, and dioxolene-derived hydroperoxides are discussed in that order. A summary of oxidations with thiazolidine hydroperoxides and our efforts toward selective heteroatom oxidations with isothiazole-1,1dione-3-hydroperoxides will be featured in section 4. Finally, miscellaneous hydroperoxides such as the less common hydroperoxyselenuranes and suspected yet structurally unconfirmed hydroperoxysulfonylamides are presented in section 5 with concluding remarks and outlook in section 6. The literature survey is from 1985 to 2006. Patents are not included. However, important earlier works are also presented for discussion where necessary. The review emphasizes synthetic significance based on suggested mechanistic considerations. For the purpose of clarity, detailed discussion of biochemical oxidation systems is beyond the scope of this review except where such a discussion is merited for the overall understanding of the review. This is mainly because it is not straightforward to draw mechanistic or synthetic consequences from enzymatic reactions to purely chemical transformations and vice versa, although the review attempts to bridge the two where possible.

2. N-Heterocyclic Hydroperoxides 2.1. 4a-Hydroperoxy Flavins and Related Systems 2.1.1. General Properties and Synthesis Flavins are cofactors involved in a host of biochemical transformations including electron transfer, dehydrogenations,

and most notably the oxidative degradation of xenobiotics (sulfides, amines, aromatics, aldehydes, etc.) by many flavoenzymes such as the hepatic microsomal FAD-containing monooxygenase (FADMO).6 The core of the natural flavin structure is the heterocyclic 7,8-dimethylisoalloxazine ring system 1. The isomeric alloxazine derivatives like 2 are usually not regarded as flavins, although some authors use these terms interchangeably (Scheme 1). In the discussions of this review, oxidations with derivatives of both structures will be treated. Flavins are able to exist in one of three oxidation states: oxidized, semiquinone radical, or fully reduced form; this ability means that they can participate in facile electrontransfer processes, which are responsible for their catalytic properties (section 2.1.2). It is generally accepted that the enzyme-bound 4ahydroperoxyflavin (Enz-4a-FlHOOH, 3), which is formed by the reductive activation of molecular oxygen with the 1,5dihydro form of flavin (FlH2), is the key intermediate in these monooxygenations (Scheme 2).7 Such intermediates have been isolated and characterized.8 This highly reactive oxidant has a half-life of 2.5 ms in native enzyme.9 The four nitrogen atoms and two carbonyl groups in the rings contribute to the electronegativity of the 4aposition and thus to the electrophilicity of the terminal peroxy oxygen atom. Their high efficiency in oxygen transfer attracted researchers to design artificial flavins as active site probes of flavoproteins in an effort to understand the mechanism of the enzymatic reactions over the years.10 The chemistry and biochemistry of flavins is extremely rich, and coverage is not attempted in this review.11 Historical aspects and biochemical significance of riboflavin and flavoproteins have been reviewed recently by Massey.12 Flavin analogues with or without substituents at the aromatic ring and/or the nitrogen atoms and stable flavinium salts have been synthesized in many different ways,13,14 which have been reviewed previously and will not be the focus of this review. Thus, the following discussions are restricted to a brief survey of aspects that are particularly relevant to organic oxidations mediated by these molecules. Some natural flavins (4 and 5) and examples of their synthetic analogues (6-11) used for studying flavoenzyme functions are shown in Scheme 3. Two general approaches have been developed for the chemical synthesis of 4a-hydroperoxyflavins (Scheme 4). These are (i) nucleophilic attack by H2O2 on oxidized flavinium cations such as 12 and (ii) reaction of molecular

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Gelalcha

Scheme 3

Scheme 4

oxygen with reduced flavins such as 9. Both methods were discovered by Kemal and Bruice, who described the first chemical synthesis of a model of the long sought for 4ahydroperoxyflavins.15 4a-Hydroperoxy-N(5)-ethyl-3-methyllumiflavin (4a-FlEt-OOH, 13) was synthesized by reaction of N(5)-ethylflavinium perchlorate (FlEt+ClO4-, 12) with H2O2 and isolated in 80% yield. Reaction of N(5)-ethyl-1,5dihydroflavin (FlEtH, 9c)13f with triplet oxygen (3O2) also gives 4a-FlEt-OOH (Scheme 4). These findings are the basis of the synthetic methods of hydroperoxyflavins and for the flavin-catalyzed oxidation reactions presented in the following sections that use either molecular oxygen or hydrogen peroxide as the ultimate oxygen sources, although in-situgenerated 4a-hydroperoxyisoalloxazines or the corresponding

4a-hydroperoxyalloxazines are the actual oxidants. Since the flavin backbone can be regenerated after oxygen transfer this access to hydroperoxyflavins either from oxygen or H2O2 incorporation can be seen as a major breakthrough in light of green organocatalytic oxidations mediated by flavins, which were realized much later (sections 2.1.4-2.1.9). It has been shown that 4a-FlEtOOH 13 slowly decomposes in water, tert-butyl alcohol, and dimethyl formamide where N(5)-ethyl-10a-spirohydantoin 14 is reported to be the final product while in CHCl3 the decomposition products depend on solvent purity.16 4a-Hydroperoxy-3,5-dialkyllumiflavins were shown by Bruice et al. to be much stronger oxidants than H2O2 or tert-butyl hydroperoxide toward sulfides, amines, and iodide and display chemiluminescence in the

Heterocyclic Hydroperoxides in Selective Oxidations Scheme 5

presence of aldehydes.15 Subsequent to these findings many research groups synthesized and studied variously substituted flavin analogues as model systems of flavoenzymes. Most of these modifications are at the periphery of the isoalloxazine ring, namely, at the aromatic ring (7, 9, and 10b,c) and/or at one or more of the nitrogen atoms (8 and 9) or even involved replacement of nitrogen atoms with carbon (6 and 11).10,14-20 Eberlein and Bruice described the synthesis and redox chemistry of unblocked and 1,5-diblocked flavins 8 (Scheme 3).17 It was established that the oxygen-donation capacity of the corresponding hydroperoxyflavins depends on the redox potential of the flavin. Ghisla et al. studied the redox properties of 6-substituted derivatives of riboflavin and 3-methyllumiflavin.18 These authors used absorption spectroscopy to reveal a strong interaction between the amino group and the isoalloxazine ring system of 6-amino-3methyllumiflavin (10b) and 6-aminoriboflavin. The redox potentials of these flavins dramatically shifted to more negative values in contrast to the natural riboflavin or the C(6)-N-acetylated analogues (10c). Massey and co-workers employed 8-substituted riboflavins 7 (Scheme 3) to study free-energy relationships in a model study of the p-hydroxybenzoate hydroxylase (PHBH) mechanism.19 In an unrelated study Ba¨ckvall and co-workers investigated the synthesis and redox properties of various aryl-substituted 1,3-dimethyl-5ethyl-5,10-dihydroalloxazins 15 (Scheme 5).20 The one-electron oxidation potentials correlated linearly with the Hammet σ values and reflected their efficiency as catalysts in the H2O2 oxidation of methyl p-tolyl sulfide. Electron-withdrawing groups (15b,c) increased the stability of the reduced catalyst.

2.1.2. Mechanism of Activation of Dioxygen and Substrate Oxidation The mechanism of flavin-catalyzed oxygen activation has been the subject of extensive investigations in the last decades and still continues to attract considerable attention.21 Some of the earliest and most fundamental mechanistic investigations on flavin-mediated monooxygenations were conducted in the 1970s and 1980s by Bruice and co-workers using model systems of flavin-dependent monooxygenases.22 In these systems it has been proposed for enzymatic monooxygenations that a rate-determining single-electron transfer occurs from reduced flavins 16 to triplet oxygen to form a flavin semiquinone-superoxide radical pair 17 (Scheme 6).17b Spin inversion leads to collapse of the radical pair to flavin peroxide anion (4a-FlH-OO-, 3-). Depending on the specific enzyme 3- can either directly participate in nucleophilic oxidations23 or be protonated to the hydroperoxide (4a-FlH-OOH, 3), which is an electrophilic oxidant.19 The resulting byproduct, flavin pseudobase FlHOH, 18, dehydrates to the oxidized flavin 19 that is reduced to 16 by NADH. Species 3 and 3- are not competent oxygen-transfer agents outside the enzyme cavity since they spontaneously eliminate

Chemical Reviews, 2007, Vol. 107, No. 7 3341

H2O2. To solve this problem Bruice et al. replaced the N(5) hydrogen with an ethyl group in the synthetic model flavin hydroperoxide, 4a-FlEt-OOH 13. With this and the analogous N(5)-methylated reagent, 4a-FlMe-OOH, the stoichiometric oxidation of sulfides, amines, and I- was achieved outside the enzyme environment. The authors proposed an SN2 displacement of the distal oxygen atom of 4a-FlEtOOH by the nucleophile with a concerted 1,2-hydrogen shift to give the corresponding flavin pseudobase, 4a-FlEt-OH, and the oxidized substrate (Scheme 7). For oxidation of 1,4-thioxane 20 to 1,4-thioxane-S-oxide 21 with 4a-FlCD3-OOH, hydrogen peroxide, and tert-butyl hydroperoxide, the ratios of the second-order rate constants in methanol at 30 °C were estimated at 1.8 × 105:25:1, respectively.14a The high rates of oxidation by hydroperoxyflavins have been suggested to be due to the low pKa (9.19.4) of the resultant flavin pseudobases which is imposed by the enhanced electronegativity of the 4a-position.24 Replacement of the N(5) nitrogen with carbon gave the corresponding C(5) secondary hydroperoxide with reduced reactivity.25 Similarly, a decrease of reactivity by factors of 3-17 was observed for the reactions of 4a-hydroperoxy-1-carba-1deaza-N(5)-ethyl-N(3)-methyllumiflavin (C(1)-4a-FlEt-OOH) derived from 11 with amines, 1,4-thioxane, and I-.26 This has been accounted for by the diminished inductive polarization of the O-O bond of the resulting C(1)-4a-FlEt-OOH due to the lower electrophilicity of the 4a-position compared to that of 13. Thus, Bruice and co-workers had shown that substitution at the 8-position of the isoalloxazine ring by the strongly electron-withdrawing CN group increases the oxidation potential and facilitates nucleophilic addition at the C4aposition.27 The 5-deaza-5-hydroperoxyflavin 22 synthesized from 23 and H2O2 also oxidized 1,4-thioxane and I- at appreciable rates but was found to be less efficient for oxidation compared to normal hydroperoxyflavins (Scheme 8).25 Bacterial luciferases28,29 catalyze the monooxygenation of long-chain aldehydes to the corresponding carboxylic acids with release of water and emission of visible light (eq 1). luciferase

1,5-H2-FMN + O2 + RCHO 98 FMN + H2O + RCO2H + light (1) In model studies of these enzymes MNDO-PM3 calculations have shown that the 4a-C site of the N(1)-deprotonated reduced flavin (5-H-FMN-) is the most energetically favored site of oxygen addition with an activation barrier of 7.4 kcal/mol, while direct addition of oxygen to the protonated 1,5-H2-FMN 16 species requires 20 kcal/mol (Scheme 9) and is therefore less favored.30 Cleavage of the 4a-C-O and O-O bonds is associated with release of H2O2 to form the oxidized flavin (also known as the dark reaction in bacterial luciferases) and substrate oxidation, respectively.31 The substrate oxidizing capacity of the hydroperoxide 3 (or the respective intermediate flavinperoxyhemiacetals in luciferase reaction) is thus expected to be dictated by the relative feasibilities of these bonds. With regard to the mechanism of oxygen-atom transfer from alkyl hydroperoxides (including native 4a-FlHOOH) to heteroatoms Bach and Su questioned the mechanism put forward by Bruice (Scheme 7) suggesting the energetic


Gelalcha

Scheme 6

Scheme 7

requirement would be too high for a concerted 1,2-hydrogen shift and therefore through-space Coulombic effects would be more important than through-bond inductive effects.32 Indeed, oxygen transfer was suggested to precede proton transfer in a two-step process (Scheme 10).33b In a more recent work the original proposal by Bruice (Scheme 7) has been endorsed.34a Oxidation of (CH3)3N, (CH3)3P, (CH3)2S, and (CH3)2Se has been related to the magnitude of an imaginary frequency for the transition state for oxygen-atom transfer. However, both experimental24 as well as theoretical34b,35 studies established that the reactivity of isoalloxazine 4a-hydroperoxide (4a-FlHOOH) lies between that of tert-butylhydroperoxide (t-BuOOH) and organic peracids. Bach estimated the gasphase reactivity of 4a-FlHOOH toward the above nucleophiles at 107-1012 times greater than that of t-BuOOH but 102-106 times less than that of peroxyformic acid (HCO3H). A difference of 0.9 kcal/mol was calculated for the intrinsic gas-phase barriers for oxidation of (CH3)3N and (CH3)2S by 4a-FlHOOH. On the basis of these calculations the authors attributed the experimentally determined value36 (more than 106 times faster rate of oxidation of amines with the enzyme bound 4a-FlHOOH compared with the model flavin 4aFlEtOOH in solution) to the greater solvation of the amine in the protic media than the influence of the protein. In fact, it was suggested that “not the enhancement of the enzyme rate but the decrease in protein-free rate should be emphasized”.34b It is well known, however, that the oxygen-donation capacity of hydroperoxides (ROOH, including peroxyacids) relates inversely to the pKa of the leaving group, i.e., on the ability of RO- to stabilize the negative charge, which is equivalent to its thermodynamic stability. This has recently been supported theoretically using common oxidants and model flavin hydroperoxides (Table 1).35 In the case of alkyl hydroperoxides, protic solvents favor the oxygen-transfer rate as a result of Lewis acid catalysis or protonation of the leaving alkoxide group, whereas the opposite trend is usually observed for oxidations by organic peracids.33a On the other hand, in support of previous studies by Anderson,37 who suggested the radical mechanism for

oxygenations by phenol hydroxylase, model studies by Mere´nyi and Lind38,39 revealed that the O-O bond in 4ahydroperoxyflavins is indeed very weak (ca. 25 kcal/mol) due to the much lower redox potential of the FlHO‚ radical40 compared to ordinary alkoxyl radicals (eq 2).

4a-FIHOOH f 4a-FIHO• + •OH ∆H° ) 25 kcal/mol (2) Thus, monooxygenations could be initiated by homolysis of O-O bond in hydrophobic enzymes such as bacterial luciferase. Recently Bach and Dmitrenko34b questioned this experimental value as being too low because they calculated BDE of about 40 kcal/mol for a model flavin hydroperoxide (26, Table 1), implying a clear disagreement between this theoretical value and the value estimated from experimental data. Further, there is no consensus on how the O-O bond dissociation energy relates to the rate of oxygen transfer from peroxides.41 Model studies by Mager also suggested the flavinhydroperoxide serves merely as a precursor to highly reactive flavinoxyl (4a-FlO‚) and hydroxyl (HO‚) radicals. The flavinoxyl radicals were suggested to be more efficient in direct aromatic hydroxylation by PHBH than the flavinhydroperoxide (see section 2.1.10).42 The possibility of aromatic hydroxylation via isoalloxazine ring cleavage43 could not be confirmed by experiment.44 Frost and Rastetter suggested that the flavin N(5)-oxide formed by rearrangement of 4aFlHOOH might effect hydroxylation of phenolates by flavoenzymes.45 However, N(3),N(10)-dimethylisoalloxazineN(5)-oxide failed to oxidize methyl 4-methylphenyl sulfide in acetic acid.46 However, recent theoretical studies34,47,48 suggested that hydroxylation of p-hydroxybenzoate 28 by PHBH proceeds by an electrophilic aromatic substitution mechanism involving intermediates 29 and 29- that lead to the final 3,4-dihydroxybenzoate 30 as shown in Scheme 11. Regardless of the various possible mechanisms research on application of synthetic flavin analogues in oxidation chemistry has been steadily growing in recent years often with impressive results. Data of the following sections have been gathered more in an effort to encourage further research than to emphasize the fact that the flavin hydroperoxides play a central role in all of these oxidations.

2.1.3. Stoichiometric Oxidation of Sulfides and Amines Oxidations of sulfides and amines are important transformations because the oxidation products (sulfoxides, sulfones,



Scheme 8

Scheme 9

Scheme 11

Scheme 10

Table 1. Calculated Activation Enthalpies of Oxygen Transfer from Hydroperoxides ROOH and pKa of the Corresponding Pseudobases ROHa

substrate CH2dCH2 cyclohexene Me2S Me2S Me2S Me2S Me2S Me2S Me2S

ROOH, R ) HCdO HCdO HCdO H CH3 t-Bu 25 26 27

pKa, ROH

∆Eq, kcal/mol

3.77 3.77 3.77 15.70 15.64 17.0 d d 9.4e

14.1 9.7 5.6 40.8,b 33.2c 27.1 30.0 10.4 11.4 d

a Data from ref 35. b H2O2-dimer. c Protonated H2O2. d Data not available. e Data from ref 24b.

hydroxylamines, nitrones, amine oxides) are key intermediates in organic synthesis.1 Stoichiometric sulfide oxidation by synthetic 4a-hydroperoxy-5-ethyl-3-methyllumiflavin 13 has been known for a long time.14a Later the method was extended to synthesis of similar flavin hydroperoxides applied to oxidation of a wider scope of substrates.24 For example, the flavinium cation 31 was treated with 1.5 equiv of H2O2 to generate the corresponding hydroperoxide 32, which was used for oxidation of sulfide 33 to sulfoxide 34. Compound 34 is an intermediate for the synthesis of spirovetivane sesquiterpenes (Scheme 12).49

The kinetics of sulfoxidation of thioanisoles, alkyl phenyl sulfides, and dialkyl sulfides by the modified flavin hydroperoxide 3214b (Scheme 13) has been described.46 For oxidation of thioanisole and para-substituted thioanisoles 35 to sulfoxides 36 the transition state for oxygen transfer was suggested to have single-electron-transfer (SET) character, while for dialkyl sulfides the transition state was described as being close to SN2. This suggestion contrasts with an earlier observation by Miller50 that rules out the electrontransfer mechanism for the sulfoxidation of thioanisoles by 32. However, Oae et al.51 provided data that suggest (in dioxane solvent, 30 °C) that the second-order rate constants for oxygen-atom transfer from 4a-FlEtOOH to aryl-substituted N,N-dimethylanilines to form the N-oxides and to the corresponding aryl-substituted methyl phenyl sulfoxides to form sulfones are comparable. The rate constants of the sulfoxidation of the corresponding thioethers are more than 30 times larger than these values. Ball and Bruice reported the facile oxidation of N,Ndimethylaniline and N,N-dimethyl benzyl amine by 4aFlEtOOH 13 to their N-oxides in high yields.52 tert-Butyl hydroperoxide and hydrogen peroxide turned out to be unreactive under the same reaction condition. Later they extended the scope of the reaction to other substrates. Thus, secondary amines, tertiary amines, and hydroxylamines gave, respectively, hydroxylamines, amine oxides, and nitrones together with 4a-FlEtOH in quantitative yields.24c However, 4a-FlEtOOH oxidized N-benzylmethylhydroxylamine 38 to a mixture of the nitrones N-benzylidenemethylamine-N-oxide 39 (53%) and N-methylenebenzylamine-N-oxide 40 (24%). Both products likely arise from dehydration of a common putative intermediate 41, the product distribution reflecting the relative ease of benzyl and methyl groups toward deprotonation (Scheme 13). Under similar conditions no evidence could be obtained for a direct bimolecular epoxidation of 2,3-dimethyl-2-butene by 4a-hydroperoxyflavins. A nucleophilic displacement of the terminal oxygen by the incoming nucleophile (N, S, I-)


Gelalcha

Scheme 12

Scheme 13

was proposed (Scheme 7). This was later confirmed by Oae et al.51,53 The results of Oae et al. showed that in contrast to the oxidations by the microsomal FAD-containing monooxygenases, which do not oxidize primary amines, the hydroperoxide 4a-FlEt-OOH oxidized all types of amines including n-octylamine and other primary amines, which were reported to actually accelerate oxidation of secondary and tertiary amines without themselves undergoing the enzymatic reaction.54 This underscores the limitations of extrapolating model system reaction rates and mechanisms to enzymatic reactions and vice versa. Benzylamine was oxidized to N-benzalhydroxylamine in 90% yield and traces of N-benzylhydroxylamine. Although the authors gave neither the amount of oxidant used nor the reaction time it is likely that the latter product is oxidized by a second molecule of oxidant to give an intermediate that eliminates water to provide the final unsaturated hydroxylamine. N-Benzylmethylamine and dimethyl aniline were oxidized to N-benzylmethylhydroxylamine and N,N-dimethyl aniline N-oxide, respectively, each in quantitative yield (Scheme 14). These authors correlated the logarithms of the secondorder oxidation rate constants with the pKa of the respective primary and tertiary amines in water and found three different correlations similar to the previous results of Bruice et al.24c As expected, tertiary amines are oxidized at the highest rates. However, oxidation rates depended on the steric bulk around the nucleophile, while the pKa values affected the oxidation rates of primary amines more than those of tertiary amines as indicated by the β values of 0.8 and 0.3, respectively. Data of the rates of oxidations of aryl-substituted dimethyl

Scheme 14

anilines implicate an electrophilic reactivity of the hydroperoxide.

2.1.4. Catalytic Oxidation of Sulfides and Amines As indicated in the Introduction extrapolation of pure enzymatic reactions to catalytic synthetic methods is not selfevident. Thus, flavin-catalyzed organic oxidations reactions with synthetic significance had to wait another breakthrough. When oxidations of thioethers and amines with H2O2 using a catalytic amount of the flavinium perchlorate 12 (FlEt+ClO4-, Scheme 4) were reported by Murahashi et al. in 198955 it was received as a milestone in flavin chemistry, which is (from the point of view of green chemistry) as significant as the previous works of Ghisla et al.13f and Bruice et al.14,15 After this breakthrough a number of organocatalytic oxidations mediated by flavins were reported which are presented in sections 2.1.4-2.1.9. In their initial work Murahashi et al. obtained excellent yields (96-99%) of several sulfoxides at room temperature with 1-10 mol % catalyst.55 For example, dibenzyl-, dibutyl-, and diphenylsulfides were oxidized to their respective sulfoxides in g96% yields with 1 equiv of H2O2 and 10 mol % of catalyst 12. Interestingly, dibenzylsulfoxide gave an excellent yield (98%) of dibenzylsulfone with 1 equiv of H2O2 and 10 mol % of catalyst, suggesting the high electrophilicity of the reactive hydroperoxide species.55

Heterocyclic Hydroperoxides in Selective Oxidations Scheme 15

Chemical Reviews, 2007, Vol. 107, No. 7 3345 Scheme 17

Scheme 18

Scheme 16

Although the best catalyst was 12 other flavin sources such as 4a-FlEtOOH itself as well as the N(5)-alkylated reduced flavins (FlEtH, 9c), FMNHEt, and FMNHMe could also be used. On the other hand, 3-methyllumiflavin (10a), riboflavin (5a), and FMN (5b) were unreactive, suggesting the importance of N(5)-protection. 4a-FlEt-OOH was identified as the active oxidant in agreement with previous works of Bruice and co-workers for the stoichiometric reaction. The kinetics of oxidation of methyl phenyl sulfide to its sulfoxide was studied in greater detail using GLC and stopped-flow spectrophotometry in methanol at 30 °C (Scheme 15). Accordingly, ionization of the flavin pseudobase (4a-FlEtOH) to the flavinium cation FlEt+ is the rate-determining step (k1 ) 0.11 s-1), while the pseudo-first-order rate constant for addition of H2O2 to FlEt+ to form 4a-FlEt-OOH is 0.7 s-1, whereas the second-order rate constant (k5′) and the rate of oxidation (υ) were, respectively, 0.18 M-1 s-1 and 3.9 mM h-1. Comparatively, the corresponding values for oxidation of dibutyl amine are k1 ) 10-4 s-1, k5′ ) 0.36 M-1 s-1, and υ ) 0.20 mM h-1 for which formation of FlEt+ was also found to be rate determining. 4a-FlEt-OOH fragments to form 10a-spirohydantoin 14 slowly at a rate of k6 ) 1.6 × 10-5 s-1. For oxidation of amines additional rate constants (k7 and k8, Scheme 15) representing nucleophilic addition to FlEt+ and dissociation of the adduct 4a-FlEtNR2 become relevant. In recent years the groups of Murahashi and Imada introduced an aerobic version of the same reactions with the flavinium perchlorates such as 12 as the catalyst.56 In this method use of H2O2 is avoided while the oxidized FlEt+ is reduced back to the flavin (FlEtH) in situ by adding 0.51.1 equiv of hydrazine hydrate (NH2NH2‚H2O) which serves as the electron and proton source to release molecular nitrogen (Scheme 16). Reduced flavin FlEtH reacts with oxygen to give the active oxidant 4a-FlEt-OOH. FlEtH is proposed to be generated in two ways. Initially the hydrazine

forms the adduct flavin hydrazide (4a-FlEt-NHNH2), which releases diazene and the reduced flavin FlEtH. On reaction with another molecule of FlEt+ the diazene forms the adduct 4a-FlEt-NdNH, which also decomposes to FlEtH and molecular nitrogen. 2,2,2-Trifluoroethanol was used as the solvent due to the high solubility of O2 in this solvent. In this way high yields of sulfoxides were obtained using molecular oxygen (1 atm) or air. Recently, the same groups applied the hydrazine system to the aerobic hydrogenation of a series of alkenes in acetonitrile in very good yields.57 Here the role of 4aFlEt-OOH is to selectively and aerobically oxidize hydrazine to generate a reactive [4a-FlEtOH NHdNH] species that reduces the substrate with release of N2. A second molecule of the alkene is reduced by the [FlEtH NHdNH] produced from the reaction of FlEt+ with hydrazine. The process is highly sensitive to solvent effects. For example, while hydrogenation of phenyl allylsulfide in the presence of 1 mo1% FlEt+ClO4-, molecular oxygen (1 atm), and 1.2 equiv of hydrazine hydrate in acetonitrile gives phenyl n-propyl sulfide in 86% yield, the mere change of solvent to the acidic 2,2,2-trifluoroethanol gives phenyl n-propyl sulfoxide in 95% yield (Scheme 17). The dramatic shift in chemoselectivity is due to the reduced nucleophilicity of hydrazine in acidic media to the extent that 4a-FlEt-OOH now preferentially transfers oxygen to sulfur. However, it is not clear whether hydrogenation of the allylic double bond or oxidation at sulfur takes place first. Aerobic oxidation of several secondary and tertiary


amines and a hydroxylamine has also been achieved in good yields by the method developed by Imada et al.58 Chemoselective oxidation of a series of sulfides to their sulfoxides58,59 and oxidation of tertiary amines to amine oxides60 by 30% aq H2O2 using the neutral 1,5-dihydroalloxazine 15a as the catalyst has been described. Under the catalytic system developed by Ba¨ckvall et al. selective sulfoxidation of thioethers in the presence of many potentially reactive electron-rich functional groups is achieved.58,59 Unlike the system discussed above further oxidation to sulfones did not occur even when a large excess of H2O2 was used over a prolonged reaction time. This suggests the high chemoselectivity of this catalyst. Vinylic sulfides required more catalyst loading and extended reaction times as well as a large excess of H2O2 compared to allylic sulfides, aryl methyl sulfides, and dialkyl sulfides due to conjugation. A conversion of only 13% was reported for sulfoxidation of diphenyl sulfide under standard conditions employing 2 mol % of catalyst. Comparison of these results with those achieved by Murahashi et al. using 12 and H2O2 raises some questions concerning the relative reactivities of the intermediates generated in each case. From the foregoing discussions regeneration of the N(5)-ethylflavinium cation 12 from 4aFlEt-OH is the rate-determining step (k1, Scheme 15). For oxidation of n-dibutyl amine (Bu2NH) to n-dibutyl hydroxylamine (Bu2NOH) k1 is 3600 times slower than k5′. However, k5′ is only 1.6 times faster than k1 for sulfoxidation of methyl phenyl sulfide. In a series of experiments Ba¨ckvall and coworkers demonstrated the far better activity of the N,N-1,3dimethyl-substituted neutral alloxazine catalyst 15a compared with the related isoalloxazine catalysts which have no substituents on the N(1) nitrogen toward sulfoxidation of methyl p-tolyl sulfide and oxidation of N,N-dimethylbenzylamine (BnNMe2) to N,N-dimethylbenzylamine-N-oxide (BnN(O)Me2). Catalyst 15a performed best, while 9c was the worst among those tested with respect to oxidation efficiency. A mechanism similar to that suggested by Bruice and discussed by Murahashi (vide supra) was proposed. Accordingly, the catalyst 15a reacts with molecular oxygen for conversion to the active oxidant 42 (Scheme 18). The hydroperoxide reacts with the nucleophiles (amines and sulfides) to give the oxidation products and the intermediate 44, which is analogous to the 4a-FlEt-OH discussed above. To explain the higher reactivity of catalysts 15a it was suggested that the rate-limiting loss of -OH from 44 (and thus regeneration of the cationic aromatic alloxazine intermediates 45 and the hydroperoxide 42) would be more favorable than the analogous reaction of 4a-FlEt-OH to give the corresponding isoalloxazinium salt, FlEt+. Perhaps it is remarkable that no successful oxidation of heteroatoms in aromatic ring systems like pyridines by hydroperoxyflavins has been reported to date.

2.1.5. Catalytic Asymmetric Oxidation of Sulfides Chiral sulfoxides are important intermediates in many transformations, and a number of methodologies have been developed to synthesize enantiomerically pure sulfoxides.61 However, only a few environmentally friendly organocatalytic ways exist for their synthesis and even less so involving flavin catalysts. The first attempt for a biomimetic catalytic asymmetric sulfoxidation using flavins was reported by Shinkai et al.62 The planar chiral flavophane (+)-46 was synthesized and used for the sulfoxidation of aryl methylsulfides such as 35a,b,h. With 35% aqueous H2O2 as the

Gelalcha Scheme 19

Scheme 20

oxygen source about 10 mol % (+)-46 relative to the aryl methyl sulfides and in a solvent mixture of H2O/MeOH at -20 °C up to 65% ee and turnover numbers of up to 8 of the corresponding enantiomerically enriched product sulfoxides could be achieved in 5 days. (R)-(+)-36a and (R)(+)-36b were obtained, while the absolute configuration of (+)-36h was not determined. Obviously the strongly electronwithdrawing CN group in the 4-position is detrimental to both the yield and the ee of the product 36h, suggesting the electrophilic nature of the hydroperoxide 48. The catalytic cycle proposed was similar to that discussed above for the racemic sulfoxidations (Scheme 19). No significant improvements have been reported ever since, although Murahashi et al. claimed the capped flavin perchlorate catalyst 49 effected the asymmetric sulfoxidation of methyl naphthylsulfide 50 to sulfoxide 51 with H2O2 in 94% yield and 72% ee (Scheme 20).63 However, details of this work are not available.

2.1.6. Role of 4a-Hydroperoxyalloxazins in the Os-Catalyzed Dihydroxylation of Alkenes The OsO4-catalyzed chemo- and stereoselective alkene dihydroxylation is undoubtedly one of the most important oxidative chemical transformations of alkenes.64 Potassium ferricyanide (K3[Fe(CN)6]), N-methylmorpholin-N-oxide (NMO), and more recently molecular oxygen have been used to reoxidize the Os(VI) back to Os(VIII).65 In 1999 Ba¨ckvall and co-workers combined the catalytic oxidation of tertiary amines with hydroperoxyalloxazins to amine oxides (section 2.1.4) with the N-methylmorpholin (NMM) mediated OsO4catalyzed dihydroxylation of alkenes to develop a novel coupled catalytic system that uses NMM and 15a as electrontransfer mediators as shown in Scheme 21.66 It was proposed that 15a enters the catalytic cycle by oxidation with molecular oxygen to 42 similar to the known


Chemical Reviews, 2007, Vol. 107, No. 7 3347 Table 3. Os-Catalyzed Asymmetric Alkene Dihydroxylation with H2O2 Using 15a as Cocatalysta

Scheme 21

entry

alkene

method

cis-diol yield (%)

ee (%)

1 2 3 4 5 6 7 8 9 10

styrene styrene R-methylstyrene R-methylstyrene trans-β-methylstyrene trans-β-methylstyrene trans-stilbeneb trans-stilbeneb 1-phenylcyclohexenec 1-phenylcyclohexenec

A B A B A B A B A B

80 75 88 81 67 61 94 89 50 58

95 95 99 90 96 99 91 90 92 70

a Data from refs 67 and 68. Method A: (DHQD)2PHAL (0.06 equiv), TEAA (2 equiv), 15a (0.05 equiv), OsO4 (0.02 equiv), NMM (0.5 equiv), alkene (1 equiv), H2O2 (1.5 equiv, 30%), 0 °C, 11-20 h. Solvent: t-BuOH/H2O: 3:1 (v/v). Method B: (DHQD)2PHAL (0.06 equiv), TEAA (2 equiv), 15a (0.05 equiv), OsO4 (0.02 equiv), alkene (1 equiv), H2O2 (1.5 equiv, 30%), 0 °C, 11-16 h. Solvent: t-BuOH/ H2O: 3:1 (v/v). b Solvent: acetone/H2O: 4:1 (v/v). c 20 h.

Scheme 22a

Table 2. Os-Catalyzed Dihydroxylation with H2O2 in the Absence (Method A) and Presence (Method B) of 15a and NMMa yield of cis-diol (%) entry

alkene

method A

method B

1 2 3 4

trans-5-decene 1-methyl-1-cyclohexene trans-2-octene R-methylstyrene

10 25 18 79

95 77 95 93

a Data from ref 66. Conditions: Method A: H2O2 (1.5 equiv, 30% aq), OsO4 (2 mol %), alkene, (1 mmol), acetone (3.8 mL), H2O (1.2 mL) 20-26 h. Method B: NMM (27 mol %), TEAA (2 equiv), 15a (5 mol %), H2O2 (1.5 equiv, 30% aq), OsO4 (2 mol %), alkene (0.5 mmol), acetone (1.9 mL), H2O (0.6 mL), 16-24 h.

reactions of reduced isoalloxazines.15 Hydroperoxide 42 is reduced to the pseudobase 44 by NMM (Schemes 18 and 21). Intermediate 44 is thought to be unstable in its neutral form60 but tautomerizes to the more stable alloxazine cation 45 which reacts with H2O2 to regenerate 42 with elimination of water. Oxidation of NMM to NMO with 42 has been shown to be 6300 times faster than the corresponding reaction with H2O2 as the oxidant. See also discussion of section 2.1.4. The amine oxide in turn reoxidizes the OsO3 produced from the reaction of alkenes to diols with the OsO4 catalyst. In this way a series of alkenes was oxidized to diols with up to 95% isolated yield with low catalyst loading (see Table 2 for selected examples).66 Although use of potassium ferricyanide has been avoided, 2 equiv of tetraethylammoium acetate (TEAA) had to be employed. The asymmetric version of this system is particularly appealing. This may be conducted, in addition to the OsO4 catalyst, either with NMM and 15a as electron-transfer mediators and in the presence of a chiral ligand67 or without NMM but with 15a and a chiral ligand on the condition that the latter contains an oxidizable tertiary nitrogen as part of its structure as demonstrated by an elegant work of Ba¨ckvall and co-workers.68 Both systems yield comparable results, but avoiding the use of NMM is preferable. Thus, by using hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2-PHAL, Scheme 21) both as a chiral ligand and as an electron-transfer mediator diol products could be obtained in excellent enantiomeric excesses and high isolated yields (up to 99%

a Conditions: (a) 3 mol % of 15a, 12 mol % of NMM, 1 mol % of K2OsO4, TEAA (0.5 equiv), 30% H2O2 (1.5 equiv), DMAP, acetone, H2O, 52.

ee and 88% yield in the case of R-methylstyrene) using H2O2 as the final oxidant (see Table 3 for selected examples). From an environmental point of view this system is clearly friendlier than the standard Sharpless asymmetric dihydroxylation (AD) which suffers from the K4Fe(CN)6 waste resulting from use of AD-mix additives. More recently the catalyst system has been immobilized in ionic liquids in its racemic version.69 Using the alloxazine 15a and running the reaction in the solvent system consisting of 4-dimethylamino pyridine (DMAP), acetone, water, and the ionic liquid 52 dihydroxylation of R-methylstyrene and 1-allyloxybenzene to their diols could be achieved in high yields. The products were separated by extraction with diethyl ether, while the immobilized catalyst could be reused by adding additional substrate and oxidant without loss of activity for at least 5 runs (Scheme 22).

2.1.7. Aromatic Hydroxylation Apart from model studies of the paradigm p-hydroxybenzoate hydroxylase (PHBH)70 oxidation of arenes using flavin catalysts is virtually unknown in modern synthetic organic chemistry. However, from an industrial, a toxicological, and a synthetic point of view the catalytic oxidative degradation of aromatic hydrocarbons with environmentally benign oxidants and catalysts is highly desirable. Understanding the mechanism of these enzymes helps design suitable catalysts for that purpose. From the discussions in section 2.1.2 various


Gelalcha

Scheme 23

mechanisms have been put forward for the mechanism of aromatic hydroxylation by PHBH where more recent works suggest an electrophilic aromatic substitution to best describe this process. The substrate p-hydroxybenzoate more likely reacts in its deprotonated phenolate form under enzymatic conditions. However, there are still questions concerning the actual oxidant under nonenzymatic conditions with synthetic isoalloxazines. In 1994 Mager and Tu reported that the one-electron reduction of the 5-ethyl-3-methyllumiflavinium cation 12 resulted in spontaneous formation the corresponding 5-ethyl3-methyllumiflavosemiquinone radical 53 and the protonated form of the flavinoxyl radical, 4a-FlEt+·-OH 54 (Scheme 23).42 At low pH the latter product was recycled to 12, thereby hydroxylating phenylalanine 55 to m-hydroxyphenylalanine 56a, o-hydroxyphenylalanine 56b, and tyrosine 56c without involvement of flavinhydroperoxide (4a-FlEt-OOH) or ·OH radicals. Since the cation 12 is in equilibrium with the flavin pseudobase, 4a-FlEt-OH, it was argued that one-electron oxidation of the latter could regenerate 54. Thus, HOPhe/ flavin ratios (total of amount of hydroxylation products per starting flavin molecule) of 0.01-0.20 corresponding to 2-40% yields of the hydroxylation products were reported, and this value increased with the acidity of the reaction medium and time to 0.98 on exposure to oxygen.42a The theoretical value is 0.50. Besides, the authors detected unknown non-peroxide intermediate X that was stable in acidic medium and further increased the yields without additional flavin in a chain process (Scheme 23). Under oxygen atmosphere or in H2O2 the yields were significantly higher and increased with decreasing acidity.42b Thus, when a mixture of phenylalanine (0.08 M) and H2O2 (4.8 × 10-2 M) and the flavinium cation 12 (1-4 × 10-4 M) were placed in nonstirred 0.1 N H2SO4 solutions at 37 °C for 24 h (complete consumption of the cation) the HOPhe/flavin ratio

was 14.69. This value increased to 31 on allowing the solution to stand for 2 days further. This increase even in the absence of the cation suggested accumulation of unidentified oxidant with a longer lifetime than the cation. Chauhan and Awashti attempted the biomimetic hydroxylation of methyl-4-hydroxybenzoate 57 with triplet oxygen as the final oxidant.71 They conducted the oxidation in AOT reverse micelles using the natural flavin mononucleotide (FMN) and sodium dithionite (Na2S2O4) to reduce it to 1,5H2-FMN at pH 7. When oxygen was bubbled for 1 h into a buffered 0.1 M AOT/isooctane solution (10 mL) consisting of methyl-4-hydroxybenzoate (0.01 mmol), FMN (0.01 mmol), and Na2S2O4 (0.1 mmol) the maximum yield of methyl-3,4-dihydroxybenzoate 58 as determined by HPLC analysis was about 20% at a water to surfactant ratio (Wo) of 15. This low yield is not surprising given the absence of stabilization of the formed hydroperoxide intermediate (4aFMN-OOH) outside the enzyme cavity. Since this yield was reduced to 4% on addition of an equimolar amount of sodium azide (NaN3) the authors concluded that the product was formed partly by a radical mechanism following homolytic cleavage of the O-O bond of the hydroperoxide (4a-FMNOOH, Scheme 24). Improvement of this process has not been reported. Despite some mechanistic progress practically relevant flavin-catalyzed aromatic hydroxylations therefore await major breakthroughs.

2.1.8. Baeyer−Villiger Oxidation of Ketones The previous sections have focused on the discussion of flavin-mediated monooxygenations by exploiting the electrophilic nature of the 4a-flavinhydroperoxides. However, as indicated in section 2.1.2, Scheme 6, 4a-flavinhydroperoxides also undergo nucleophilic reactions with appropriate electrophilic substrates. The Baeyer-Villiger (BV) oxidation of ketones to lactones or esters is an example of such a shift in the reactivity of hydroperoxyflavins. Lactones are key



Scheme 24

Scheme 25

Scheme 26. Proposed Mechanism of CHMO (simplified)23

intermediates both in nature and in the synthesis of fine chemicals and pharmaceuticals. In the laboratory the BV reaction is usually conducted with organic peracids as the oxidants where the initial products are thought to be adducts 59 (Scheme 25, a) known as Criegee intermediates that rearrange to the final products. Historical perspectives and mechanistic aspects72 as well as modern synthetic advances73 of the BV reaction have been reviewed previously. In nature this transformation is carried out by flavoenzymes such as cyclohexanone monooxygenases (CHMO, Scheme 25, b).23 Baeyer-Villiger monooxygenases use molecular oxygen and a stoichiometric amount of NAD(P)H to catalyze the smooth and mild conversion of nonaromatic cyclic and acyclic ketones to lactones or esters, respectively, usually with synthetically interesting high stereoselectivities. Mechanistically there has been considerable uncertainty over whether the enol tautomer of the ketone reacts as a nucleophile with the terminal oxygen of 4a-hydroperoxyflavin intermediates (4a-FlHOOH) as the electrophile or the deprotonated form of this species (4a-FlH-OO-, Scheme 6) acts as the nucleophile to attack the electrophilic carbonyl function of the ketones.74 Both pathways lead to the same product. However, recently Massay et al.23 presented evidence in support of the latter route for cyclohexanone as the substrate. In this case the ketone reacts with enzyme-bound 4a-peroxyflavin intermediate to form the hemiacetal (Criegee adduct, 59′) that rearranges to products following simulta-

neous heterolytic cleavage of the O-O bond and 1,2migration of one of the alkyl groups at the carbonyl function (Criegee rearrangement, Scheme 26). This section deals with the progress made toward the biomimetic BV oxidations in recent years employing synthetic flavins as catalysts. Mazzini et al. described the first flavin-catalyzed BV oxidation of ketones. By using the flavinium salt 6075 and H2O2 as the oxygen source ketones 61a-c were converted to the expected lactones 62a-c in good yields (Scheme 27, reactions a-c) under mild conditions.76 An interesting feature of this system is that under appropriate reaction conditions the double bond (reaction b) and the alkoxy group alpha to the carbonyl function (reaction c) are tolerated with negligible background reaction. Thus, the reaction is both chemo- and regioselective. The catalytic cycle analogous to that discussed by Murahashi for catalytic oxidation of sulfides and amines using catalyst 12 (Scheme 15, section 2.1.4) was rationalized as involving initial formation of hydroperoxide 63 by reaction of H2O2 and 60 and oxygen delivery from 63 to ketone substrates to give the lactones and the pseudobase 64 as shown in Scheme 28. Not surprisingly, the corresponding N(5)-dealkylated neutral catalyst 65 was inactive while use of molecular

3350 Chemical Reviews, 2007, Vol. 107, No. 7 Scheme 27a

Gelalcha Scheme 30a

a Conditions: (a) 35% H O (2 equiv), 5 mol % of 60, 6 h, rt, t-BuOH 2 2 as solvent. (b) H2O2 and 60 as for conditions a, 8 h, -5 °C i-PrOH as solvent. (c) Same as conditions a but 24 h.

Scheme 28

a Conditions: Zn (1.5 equiv), 2 mol % of 66, 60 °C, O (1 atm), CH CN/ 2 3 EtOAc/H2O (8:1:1 v/v) as solvent. (a) 7 h. (b) 4 mol % of 66, 8 h. (c) 4 h. (d and e) reaction time not available.

Scheme 29a

a Steps: (1) HCHO, HCI, 60 °C, 3 days. (2) CH I, K CO , DMF, rt, 3 3 2 overnight. (3) CH3CHO, NaBH3CN, Na2S2O4, DMF, 60 °C, 2 h. (4) NaNO4, HCi4, NaCIO4, 0 °C.

oxygen gave only

Heterocyclic Hydroperoxides in Selective Oxidations - Chemical

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