Organic Reaction Mechanisms Series

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Chapter 3: Oxidation and Reduction by R. N. Mehrotra from Organic Reaction Mechanisms 2015

Chapter 4: Carbenes and Nitrenes by E. Gras and S. Chassaing from Organic Reaction Mechanisms 2015

Discover more about the Organic Reaction Mechanisms Series: https://onlinelibrary.wiley.com/series/1200 CHAPTER 3 Oxidation and Reduction

R. N. Mehrotra Formerly of Department of Chemistry, Jai Narain Vyas University, Jodhpur, India

Reviews and Highlights ...... 107 Oxidation by Metal Ions and Related Species ...... 116 Magnesium ...... 116 Chromium, Manganese, and Nickel ...... 116 Copper, Silver, Gold, and Thallium ...... 122 Cerium, Samarium, Titanium, Cobalt, Vanadium, Tungsten, Rhenium, and Molybdenum ...... 129 Platinum and Iridium ...... 135 Group VIII Metals: Iron, Palladium, Rhodium, Ruthenium, and Osmium .... 140 Oxidation by Compounds of Non-metallic Elements ...... 170 Sulfur and Boron ...... 170 Halogens ...... 174 Peracids ...... 178 Ozonolysis and Ozonation ...... 178 Singlet Oxygen ...... 183 Triplet Oxygen and Autoxidation ...... 183 Other Oxidations ...... 184 Reductions ...... 189 Other Reactions ...... 193 References ...... 208

Reviews and Highlights A number of review articles, book chapters, and research reports were published during the year under review. A large number of these are related to aspects of oxidation followed by reduction including hydrogenation and transfer hydrogenation, and one each on hydroboration of carbonyl derivatives and hydrosulfurization and hydrodenitrogenation. 1 The review on the bio-inspired oxidations of aliphatic C–H groups with H2O2 in IV IV the presence of manganese complexes traces the first use ofL [ Mn (O)3Mn L](PF6)2 (L = 1,4,7-trimethyl-1,4,7-triaza cyclononane (Me3tacn)), the Wieghardt’s dinuclear Mn(IV) complex2 as the catalyst for the oxygenation of alkanes (hexane, cyclohexane, cycloheptane) in acetonitrile.3 The catalyst had 1350 turnovers in the presence of acetic acid, which is the best catalytic additive among the carboxylic acids. The Me3tacn- catalysed oxidation of cis- and trans-1,2-dimethylcyclohexanes in the presence of

Organic Reaction Mechanisms 2015, First Edition. Edited by A. C. Knipe. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. 107 108 Organic Reaction Mechanisms 2015 sodium oxalate is highly stereo-retentive (>99% retention of configuration), which is considered as evidence against radical-type oxidation.4 The other Mn complexes that act as the catalyst in H2O2 oxidations are polymer- bound Mn(IV)-1,4,7-triazacyclonone for hydrocarbons,5 Mn complexes containing 1,4,7-trimethyl-1,4,7-triazacyclononane-derived ligands that are useful catalysts for the oxidation of olefins, alkanes, and alcohols,6 the Mn(II) complex with (1-(bis((pyridin- 2-yl)methyl)amino)-3-chloropropan-2-ol)(𝜂𝜂1-NO3)(𝜂𝜂2-NO3) which is a moderate catalyst in the oxidation of cyclohexane (upto 62 turnovers),7 the Mn(III) complex obtained by reacting the macrocyle ligand (1) with MnCl2, in the oxidation of various alkenes, alkanes, and aromatic compounds,8 and the complexes [((S,S)-N,N′-bis(2- ′ pyridylmethyl)-N,N -dimethyl-trans-1,2-diaminocyclohexane)Mn(CF3SO3)2] and (1S, ′ ′ 2S-N,N -dimethyl-N,N -bis((pyridine-2-yl)methyl)cyclohexane)Mn(CF3SO3)2)(A) in the oxidation of cis-1,2-dimethylcyclohexane.9

H O N C

N N

N C H O (1)

The complexes [2-(((S)-2-((S)-1-((pyridin-2-yl)methyl)pyrrolidin-2-yl)pyrolidin-1- yl)methyl)pyridine Mn(CF3SO3)2], (A), and [N-methyl-N-((pyridin-2-yl)\methyl)((S)- 1-((pyridin-2-yl)methyl) pyrrolidin-2-yl)methanamine Mn(CF3SO3)2], (B), act as catalysts in the oxidation of a variety of secondary and tertiary alkanes in the presence of acetic acid (up to 970 catalytic turnovers). The cylcohexanol/cyclohexanone ratios of 4.9 : 5.1 point to a metal-based rather than radical-driven oxidation pathway.10a The complexes (A) and (B) also catalysed the enantioselective epoxidation of various olefins with AcOOH and H2O2/AcOH with high efficiency (up to 1000 turnover numbers (TONs)).10b The Mn complex with (N-methyl-N-((1-methyl-1H-benzo[d]imidazol-2- yl)methyl)((S)-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-2-yl)methanamine) is reported to catalyse the oxygenation of secondary benzylic and aliphatic C–H bonds in the presence of an acetic acid additive with the predominant formation of ketones (up to 154 TON).11 Further insights into the hydrogen-abstraction mechanism and oxygen-transfer step have been provided by a study involving the complex B and the complexes with the ligands 4-methoxy-2-((2-(1-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)pyrrolidin-2- yl)pyrrolidin-1-yl)methyl)-3,5-dimethylpyridine and 2-((2-(1-((4-(dimethylamino)-3,5- dimethylpyridin-2-yl)methyl)pyrrolidin-2-yl)pyrrolidin-1-yl)methyl)-N,N,3,5-tetra- methylpyridin-4-amine.12 The review on Pd(II)-catalysed oxidation of alkenes is focused mainly on (i) oxidations that proceed via cleavage of allylic C–H bond and the formation of a 𝜋𝜋-allyl complex, 3 Oxidation and Reduction 109

(ii) Wacker-type oxidations that proceed via nucleopalladation followed by 𝛽𝛽-hydride elimination, and (iii) 1,2-difunctionalization of alkenes that proceeds via nucleopalladation followed by functionalization of the resulting 𝜎𝜎-alkylpalladium(II) intermediate. The mechanisms of each type of reactions are discussed with their scope and limitations for formation of new C–O or C–N bonds.13 The digest ‘Transition-metal-catalysed etherification of unactivated C–H bonds’ summarizes recent advances using different directing groups and catalyst systems for C(sp2)–H and C(sp3)–H bond activation. Despite the advances made, there are still some reactions that suffer from limited substrate scope, harsh reaction conditions, high catalyst loading, and the use of synthetically restricted directing groups. Some of the fundamental challenges such as (i) the development of an efficient catalyst system for the alkoxylation of unactivated C(sp3)–H bonds, (ii) the application of these transformations into the total synthesis of natural products, and (iii) an insightful understanding of the detailed mechanism that could help to design more efficient catalyst systems are yet to be addressed.14 Recent advances in the synthesis of chiral building blocks that use rhodium-catalysed asymmetric hydrogenation of olefins are discussed in a digest letter. Examples that have broadened the scope of the hydrogenation of enamides and enol esters are discussed in the first part, and the hydrogenation of substrates such as unsaturated carboxylic acids, nitroderivatives, or phosphonates, among others, are focused in the second part.15 A review titled ‘Quinone-catalysed selective oxidation of organic substrates’ focuses on the catalytic reactivity of quinones with high reduction potential, namely (2,3-dichloro- 5,6-dicyano-1,4-benzoquinone (DDQ)) and chloranil, which operate through a hydride abstraction mechanisms and typically react with electron-rich substrates capable of stabilizing carbocationic intermediates. The examples of single-electron transfer and addition–elimination reactions are also implicated with these quinones. Differences in the reactivity between DDQ and chloranil are typically rationalized on the basis of their differential reduction potentials, but the findings in the literature suggest that reactivities observed across diverse quinone structure types do not exhibit simple linear free-energy correlations. Instead, the reactivity is closely linked to the reaction pathways accessible to the different quinone structures. The second class of quinone consists of o-quinone catalysts that are shown to be com- patible with electrochemical and aerobic catalytic turnover. Mechanistic studies have shown that these quinones engage in electrophilic reaction pathways such as transam- ination and addition–elimination mechanisms, which introduce kinetically accessible pathways not readily available to the more oxidizing p-quinones. There has been significant progress in developing catalytic methods where the quinone is used in combination with a more desirable terminal oxidant.16 A brief summary of the recent developments in I2-catatalysed oxidative coupling reactions that utilize C–H and X–H (X = C, N, O, S, P, etc.) as nucleophiles and of the different roles of the catalyst is presented in a review. The authors feel that enantioselective intermolecular reactions could be a promising development in future. The reaction conditions are generally mild and the compatibility of the substrate is good. Examples are considered with KI, n-Bu4NI (TBAI), I2, and different iodoarenes as the most used catalysts, while t-butyl hydroperoxide (TBHP), m-chloroperoxybenzoic acid (m-CPBA), H2O2, and AcOOH are the mostly used oxidants. Various reaction mechanisms are 110 Organic Reaction Mechanisms 2015 discussed in which different iodine species act as key intermediates. The mechanistic role of iodine catalysts is still largely unclear, though direct evidence of the reaction mechanism is available in a few examples.17 A review summarizes some efficient catalytic systems for the selective dehydrogenation (oxidation) of alcohols to the desired carbonyl compounds (aldehydes or ketones). The choice of suitable catalysts and oxidants is the key to achieving the dehydrogenation reactions with high efficiency. Oxidants such as3 CrO , KMnO4, MnO2, SeO2, and Br2 (toxic) are suggested to be replaced by O2 and aqueous H2O2 (clean oxidants). The small amount of RuCl2(PPh3)3 TEMPO (TEMPO = (2,2,6,6- tetramethyl piperidin-1-yl)oxyl) effectively catalyses the aerobic oxidation of a broad range of alcohols, whereas Au/CuO is the recyclable catalyst for the O2 oxidation of the alcohols. Photo-oxidation of alcohols over Nb2O5 proceeds through a unique photo-activation mechanism. Catalytic acceptor-less dehydrogenation (AD) of alcohols to generate H2 and a more reactive carbonyl group are attracting more research attention. The AD reactions produce only H2, a useful source of green energy, and eliminate the production of organic/inorganic side waste products.18 A review has summarized the remarkable achievements made in the formation of imines from alcohols and amines using O2 or air as the terminal oxidant. The three new approaches considered are (i) the cross-coupling of alcohols with amines, (ii) the self-coupling of primarily amines, (iii) and the oxidative dehydrogenation of secondary amines. The related catalysts are classified into metal (Cu, Fe, Al, V, Ce, Mn, Pd,Au, Ag, Ir, Ru, Pt/Sn), metal-free, and photo- and bio-inspired catalysts. The review places particular emphasis on the low-cost, high-active, and versatile catalysts.19 A journey through the most innovative and wonderful applications of the ‘Ireland’ one- pot alcohol oxidation coupling reactions is described in a review article to celebrate 30 years of diverse synthesis. While devising synthetic routes to polyether ionophore antibi- otics in 1985, several highly reactive aldehydes were encountered, but their isolation and subsequent elaboration proved difficult. The problem was circumvented by adopting a synthetic route in which the alcohol was oxidized to the aldehyde and a nucleophile was added to the crude oxidized mixture. The process was subsequently adapted by many research groups the world over. The method is dubbed the ‘Ireland’ oxidative process, which proved to be highly successful.20 The area of acetal and ketal reduction to ethers has expanded significantly because of a greater understanding of the roles of the activating and reducing agents. Thus there is a review on the reduction of O,O-, N,O-, and S,O-acetals to ethers. It covers advances in the field with a focus on the factors that control regioselective reduction in awiderange of applications as well as on the methods that enable highly selective reduction of one of the C–O bonds under mild and functional-group-tolerant conditions.21 The kinetics and mechanism of {Ni(II) (acac)2 + L2}-catalysed oxidation of toluene and cumene with O2 is reviewed, where L2 = donor additive N-methylpyrrolidone-2 and is used to modify the activity of the Ni(II) catalyst to increase the yield of ROOH. The routes for the formation of the major oxidation products of toluene vary depending on a parity of components in the catalytic systems and are defined by the nature of the active complexes formed in situ during oxidation. Changes in the mechanism of formation of cumene oxidation products are not observed.22 3 Oxidation and Reduction 111

A review of O3 degradation of alcohols, ketones, ethers, and hydroxybenzenes describes the dependences of the kinetics, mechanism, and thermodynamics of the ozonation reactions on the structure of the compounds, on the medium, and on the reaction conditions; various possible applications of ozonolysis are specified and discussed.23 The development of metal-free oxidative C–C bond formation through C–H bond functionalization is the subject of a mini-review, which focuses on the most important examples from this area. Only those reactions that involve C–C bond formation through oxidation of two C–H bonds are included. The review has three main sections: (a) C(sp2)–C(sp2) bond formation, (b) C(sp2)–C(sp3) bond formation, and (c) C(sp3)–C(sp3) bond formation. The development of transformations using inexpensive and environmentally friendly oxidants, such as simple peroxides and oxygen, is still a challenge. The need to develop more oxidative C(sp3)–C bond-forming reactions from abundantly available C–H bonds in hydrocarbons is also emphasized because this would present an opportunity to develop highly attractive stereoselective versions of these reactions.24 The most versatile method for the oxidative C–H/C–H cross-coupling reactions to form C–C bonds is to use transition-metal oxidants including copper or silver salts in stoichiometric amount in the presence of highly priced metal catalysts such as Rh, Pd, and Ru. However, the high-priced metal catalysts have been recently replaced by copper or silver salts using oxygen or even air as the ultimate oxidant. This development, which is still in its infancy, has considerably reduced the financial cost and has also resulted in atom economy. The review points out that most of the reported reactions are not yet truly general because there are many substrate limitations, and suggests that there are ample opportunities in discovering useful transformations, expanding substrate scope, improving chemo and regioselectivity, innovating reaction systems, and clarifying the reaction mechanisms for transition-metal-mediated oxidative C–H/C–H cross-coupling reactions.25 The review ‘Oxidative coupling reactions at Ru(0) and their applications to catalytic homo- and cross-dimerization’ is concerned with the aspects and use of the Ru(0) complexes having a cyclic diene ligand in homo- and cross-dimerization. The unequivocal evidence for the Ru(0)-catalysed oxidative coupling mechanism in a stoichiometric organometallic reaction and the isolation of a ruthenacyclopentane as a key intermediate in the catalytic dimerization of methyl acrylate are the breakthroughs that have led to the first enantioselective cross-dimerization between conjugated dienes and substituted alkenes.26 The peroxide intermediates in the oxidation processes are reviewed, with a focus on the synthesis, structure, and reactions of organic trioxides ROOOR (R = H or an organic radical), which are close analogs of peroxides in terms of their properties and characteristic reactions. The review discusses the spectral identification, structure, thermal stability, and chemical properties of HOOOH, HOOO⋅, hydrotrioxides, and open-chain and cyclic trioxides (including fullerene ozonides). The chemical reactions that these compounds undergo resemble those of peroxides and occur at low temperatures. The most typical reaction of trioxides is the homolytic decomposition at one of the O–O bonds. Trioxides are likely to induce and catalyse the decomposition. Hydrotrioxides show 112 Organic Reaction Mechanisms 2015 high oxidative activity. Singlet oxygen is generated during the decomposition of some trioxides.27 The structure, spectral properties, methods of generation, reactivity, and mechanisms of various transformations of nitroso oxides (the labile peroxide species with the general formula RNOO) in both gaseous and the condensed media have been reviewed. The nitroso oxides are intermediates in the thermal and photochemical reactions, proceeding with the participation of triplet nitrenes in the presence of molecular oxygen.28 The present review focuses on the study of Fe(IV) chemistry, particularly non-heme iron(IV) complexes that were discovered a decade ago, since it leads to advances in environmentally friendly chemical syntheses. Fe(IV) is employed in Nature for oxidation in a wide variety of reactions in both heme and non-heme active sites. Fe(IV) catalytic cycles are now known for several oxidation reactions, which range from epoxidation to sulfoxide formation. Yet, there are still several aspects of these catalysts that must be improved before their general application in organic synthesis. The review suggests that the selectivity of the reactions must be tested on a wider variety of substrates. It is pointed out that none of the examples has been prepared with a chiral iron catalyst that imparts enantioselectivity to the substrate. Nevertheless, the review concludes that the advantage of employing high-valent iron versus other metals could be substantial.29 The reduction of secondary and tertiary phosphine oxides to phosphines is a challenging field of research because achiral or chiral phosphines are widely used as versatile ligands for transition-metal-catalysed reactions and as useful reagents in a number of organic transformations (Wittig, Staudinger, Mitsunobu, Baylis–Hillman, and Appel reactions, among others). Therefore, it has always been a challenge to obtain optically pure phosphine. The reduction of phosphine oxides is the simplest method to obtain phosphines. Silane reduction of P-chiral phosphine oxides leads to phosphines with retention or inversion of configuration at the phosphorus atom depending on the presence of additives (amine or catalyst). Titanium-catalysed reductions of phosphine oxides by silanes take place at lower temperatures and in shorter times. Tetramethyldisiloxane has been efficiently used for the large-scale production of phosphines. The essential difficulty is the strength of the =P=O bond, which involves new procedures to main- tain high chemio and stereoselectivity. In fact, the reactivity of the phosphine oxides and the mechanism of the reduction are not always well understood. Some mechanistic pathways for the reduction of phosphine oxides have been proposed from the dynamic stereochemistry and based on density functional theory (DFT) calculations. This review presents a comprehensive and critical overview of the methodologies developed in the last decade to obtain optically pure tertiary phosphines from P-stereogenic phosphine oxides.30 A review of sulfoxide redox chemistry with molybdenum catalysis analyses the role of MoO2Cl2(H2O)2 in solution, which catalyses the oxidation of sulfides and sulfoxides by H2O2 to sulfoxides and sulfones, respectively, and catalyses the reduction of sulfoxides to sulfides in the presence of catecholborane (HBcat). The mechanism ofthe oxidation of sulfoxide and its reduction is discussed. Other Mo(VI) complexes do catalyse the oxidation of sulfide to sulfone, but the oxidation of sulfoxide to sulfone isless well documented. The reduction mechanism differs from the one with Re(V) complexes, which formally oxidize to the Re(VII) state at some point of the catalytic cycle, which 3 Oxidation and Reduction 113 cannot happen to the Mo(VI) species. DFT calculations show that the reaction control is associated with the first step, that is, activation of the X–H31 bond. An appraisal of the current knowledge on asymmetric Ir-catalysed direct hydrogenations of a number of acyclic and cyclic imines is presented in a review, which gives a summary of the most interesting catalysts with respect to selectivity, activity, and substrate scope. It also discusses the effects of different reaction conditions on the enantioselectivity of imine reduction. A detailed analysis of the proposed imine hydrogenation mechanisms reveals that an outer-sphere mechanism is operative, though few of these involve coordination of the imine to the iridium center. The mechanistic proposals put forward to explain the enantiodiscrimination of selected complexes are reviewed, showing that the stereocontrol is likely to be governed by weak non-bonding interactions between the substrate and the chiral catalyst complex. The selectivity-determining interactions might be modified through the coordination of the solvent, additive, or product molecules to the iridium complex, providing a rationale for the effect of the solvent or additives on the enantioselectivity. A few catalyst systems with improved activities in terms of TON have also been reported.32 Asymmetric transfer hydrogenation of ketones works properly for aromatic and heterocyclic ketones only; the application to aliphatic ketones is very restricted, giving poor yields and enantioselectivities. The subject matter is reviewed from 2008 to 2015. The most effective organometallic compounds (derived from Ru, Rh, Ir, Fe, Os, Ni, Co, and Re) and chiral ligands (derived from amino alcohols, diamines, sulfur- and phosphorus-containing compounds, as well as heterocyclic systems) are shown. Spe- cial attention is paid to functionalized substrates, tandem reactions, processes under non-conventional conditions, supported catalysts, dynamic kinetic resolutions, the use of water as a green solvent, theoretical and experimental studies on reaction mechanisms, enzymatic processes, and finally applications to the total synthesis of biologically active 33 organic molecules. ee Recent advances in catalytic hydroboration reaction of carbonyl compounds, imine derivatives, and carbon dioxide are intensively reviewed; advances in the catalytic hydroboration of unsaturated organic compounds, specifically those involving C–X (X = N, O) bonds, are outlined. It is found that both transition metals and main-group metal compounds exhibit efficient catalytic ability in the hydroboration reaction. Theoretical studies support the experimental data in understanding details of the reaction mechanism. The reaction mechanism for the hydroboration of carbonyl and imine derivatives with transition-metal catalysts involves multiple pathways, whereas those catalysed by main-group metals are relatively simple. The initial activation of CO2 prior to product formation is a feature of most of its hydrobortion reactions. The potential of hydroboration reactions is not limited to the addition of H–B bonds across unsaturated bonds. The reduction of CO2 affords a variety of compounds, and it is concluded that future work with main-group catalysts will involve hydroboration of other unsaturated bonds rarely explored thus far.34 Recent experimental and computational studies related to the crucial effect of solvent and additive on the nature of the active catalytic species in palladium-catalysed cross- coupling reactions, the non-synergistic and oxidizing effect of Cu salt additives on the (pre)catalyst, and the chemistry derived from binuclear palladium complexes of low and 114 Organic Reaction Mechanisms 2015 high oxidation states are reviewed. The direct correlation of computational predictions with experiments is likely to reveal information with respect to the performance of computational methodology.35 The chapter ‘Iron-promoted reduction reactions’ reviews the reactions from the stand- point of the catalyst design. Participation of the ligand in the catalytic cycle is clearly demonstrated by the PNNP, (1S,2S)-N,N′-bis-[o-(diphenylphosphino)benzylidene] cyclohexane-1,2-diamine, complexes, Shvo-type complexes, and the iron-pincer complexes because both the iron center and the ligand are responsible for hydrogen transfer from the iron complex to the C=O group in the outer coordination sphere. These three Fe complexes are active for catalytic hydrogenation or transfer hydrogenation reactions having CO ligands beside the hydrosilylation reactions. The reduction mechanisms are in line with the concept of Noyori’s metal–ligand bifunctional catalysis. The redox-active bis(imino)pyridine ligand is crucially important for the highly efficient Fe-catalysed hydrogenation and hydrosilylation of alkenes.36 Hydrodesulfurization (HDS) and hydrodenitrogenation (HDN) are the reactions of organosulfur and organonitrogen compounds with hydrogen over a metal catalyst for the removal of S as H2S and N as NH3 with simultaneous formation of the corresponding hydrocarbons. This is how S and N are removed from petroleum feedstock in refineries. The hydrogenation of the heterocyclic rings is accomplished by late transition metals; the early transition metals cleave the C–N bond of heteroaromatic rings. The electron-rich metals (Ru, Ni) cleave C–N bonds in non-aromatic amines. The mechanisms reported so far in these cases suggest either an intramolecular nucleophilic attack by a metal hydride, or protonation of the N atom followed by elimination of ammonia or an amine, similar to the accepted denitrogenation mechanisms. Considering the complexity of the HDN mechanisms, homogeneous modeling studies must be undertaken with the necessary caution. Nonetheless, many reactions described involving transition-metal complexes with N-heterocycles or other N-ligands show some striking analogies with related reactions occurring on the surface of heterogeneous catalysts. Organometallic HDN modeling is far behind HDS modeling, but the research described in this review opens the way for further work on this field of molecular analogs of surface species and interactions.37 The concept of a frustrated Lewis pair (FLP) is based on the notion that combinations of Lewis acids and bases that are sterically prevented from forming classical Lewis acid–base adduct have Lewis acidity and basicity available for interaction with a third molecule. A recent account38 has featured three examples of such developments: hydrogenation, hydroamination, and reduction of CO2. The dramatic discovery that FLPs can activate H2 broke the long-prevailing belief that only metals can do so. Subsequently, simple main-group species were used as catalysts for the hydrogenation of imines, enamines, silyl enol ethers, olefins, and alkynes. FLPs have found use in the reduction of aromatic anilines, N-heterocycles, and ketones. A number of zwitterionic products, obtained from the combination of a number of acids and bases, are found to catalyse the hydroamination of alkynes providing a metal- free route to anamines. Initially, FLPs were shown to capture CO2, the greenhouse gas. Later, the stoichiometric reduction of CO2 to either methanol or CO was achieved by modifying the con- stituents of the FLPs. The reduction of CO2 by hydrosilylation and hydroboration or 3 Oxidation and Reduction 115 deoxygenation was achieved by further modifications. It is thus clear that FLPs provide a new approach for the design and application of main-group chemistry and development of metal-free catalytic processes. A review39 of the oxidative coupling between two hydrocarbons summarizes the developments made in the last 4 years and highlights catalysis by palladium (most popular catalyst), copper (gaining popularity), rhodium, and ruthenium. Transition-metal-free oxidative couplings (currently drawing much attention) and catalyses by other transition metals are also being tried. Couplings between (i) Csp–H and Csp2–H, (ii) Csp2–H and Csp2–H, (iii) arene and alkene, (iv) alkene and alkene, (v) arene and arene, (vi) arene and aldehyde, and (vii) Csp3–H related oxidative cross-couplings are discussed under Pd catalysis. Similarly, couplings (i), (ii), (iii), (iv), and those between (viii) Csp–H and Csp3–H, (ix), Csp2–H and Csp3–H, and (x) Csp3–H and Csp3–H are discussed under copper catalysis. The couplings (v) and (vi) find mention under Rh catalysis and (iii), (iv), and (xi) alkane-related coupling are discussed under Ru catalysis. The authors conclude that, despite numerous investigations, there remain problems such as (a) the reaction conditions are still not mild enough, (b) the reaction efficiency still remains very low, and (c) there is little understanding of C–H functionalization mechanisms. An account40 has been given of the remarkably high catalytic activity of the Os complexes (2–4), [OsCl2(PP)(NN)] (PP = diphosphine ; NN = diamine, 2-aminomethyl pyridine), and pincer [OsCl(CNN)(PP)] (HCNN = 6-aryl-2-aminomethylpyridine, 2-aminomethylbenzo[h]quinoline) in the hydrogenation and transfer hydrogenation of ketones, aldehydes, esters, and imines, in the hydrogenation of C–O and C–N bonds, and in the synthesis of chiral and non-chiral alcohols and amines in high yields with very short reaction times. TONs and turn-over frequencies (TOFs) up to 105 and 106 h−1, respectively, are achieved. Moreover, the high productivity and thermal stability and simple syntheses of Os complexes may offset their higher cost compared with their Ru analogs. The Os complexes catalyse transfer hydrogenation and hydrogenation reactions as well as dehydrogenation of alcohols with efficiencies comparable and in some cases superior to those reported for the analogous ruthenium systems. The results give a glimpse of the potential of Os for the design of new, highly productive, and robust catalysts for the synthesis of chiral and non-chiral alcohols and amines as well as carbonyl compounds from alcohols.

R1 i Pr 2P H CO H Os Cl 2 P N HN N P • Os N Os • P N Cl H Cl Cl P 2 NH2

R2 (2)(3) (4)

The control of regiochemistry in the Ni-catalysed reductive couplings of unsymmetrical 𝜋𝜋-components is a challenge, for which complementary solutions 116 Organic Reaction Mechanisms 2015 have been developed during the studies of aldehyde–alkyne combinations. Effective protocols that allow highly selective access to either regiosiomer of the allylic alcohol (products) using a wide range of unsymmetrical alkynes could be established by carefully selecting the ligand and reductant, as well as temperature and concentration. An understanding of the origin of the regioselectivity control was provided by computational studies and an evaluation of the reaction kinetics. The development of ligand–substrate interactions played an essential role, and the overall kinetic descriptions differed between protocols. Rational alteration of the rate-determining step has a key role in the regiochemistry reversal strategy, and in one instance the two possible regioisomeric outcomes in a single reaction were found to operate by different kinetic descriptions. The insights suggest simple and predictable experimental variables to achieve a desired reaction outcome. The work has provided an illustration of how insights into the kinetics and mechanism of a catalytic process can rationalize subtle empirical findings and suggests simple and rational modifications in procedure to access a desirable reaction outcome. Furthermore, these studies presented an illustration of how important challenges in organic synthesis can be met by novel reactivity afforded by base metal catalysis. The use of nickel catalysts in this instance not only provides an inexpensive and sustainable method for catalysis but also enables unique reactivity patterns not accessible to other metals.41 In the following narration, the order of reaction with respect to a reagent is not men- tioned if it is first order. The kobs refers to the observed pseudo-first-order rate constant and its unit is (s−1). The activation parameters are ignored if these have no mechanisitic significance. Mechanisms that are unique are graphically represented.

Oxidation by Metal Ions and Related Species Magnesium

The 𝛽𝛽-diketiminato magnesium alkyl complex (5) is the catalyst for the hydroboration of organic isonitriles, RNC, with pinacolborane (HBpin). The reaction proceeds under mild conditions when R = alkyl and provides access to the corresponding 1,2-diborylated amine products. Reaction with the cyclohexyl, 1-pentyl, and t-butyl isonitriles afforded the N-alkylated 1,2-bis(boryl)amines as the only products.42 Me Ar N Mg Me N Me Ar (5)

Chromium, Manganese, and Nickel The oxidation of phenylsulfinylacetic acidPSAA ( ) by chromic acid (Cr(VI)) in 20% MeCN–80% H2O water (v/v) to MePh sulfone is first order each in PSAA, Cr(VI), + + and [H ] (HClO4). The active oxidizing species is HCrO3 . The reaction mechanism 3 Oxidation and Reduction 117 involves the rate-determining nucleophilic attack of the sulfur atom of PSAA on Cr + of HCrO3 forming a sulfonium ion intermediate. The intermediate then undergoes 𝛼𝛼,𝛽𝛽-cleavage, leading to the liberation of CO2. The negative reaction constant 𝜌𝜌 indicates that the sulfur center in the transition state (TS) is electron deficient. The existence of an isokinetic relationship and operation of the structure–reactivity principle confirm that all the meta- and para-substituted phenylsulfinylacetic acids follow the same mechanism.43 The best combination of the promoter (picolinic acid (PA), quinolinic acid (2,3-PDA), and dipicolinic acid (2,6-PDA)) and the micellar catalyst (sodium dodecyl sulfate (SDS), N-cetylpyridinium chloride (CPC), and TX-100)) has been investigated for chromic acid oxidation of 2-butanol to 2-butanone. The most efficient combination is found to be SDS/2,3-PDA. The mechanisms for the unpromoted and promoted reaction paths are suggested.44 In a similar study on the oxidation of formaldehyde, the best combination is 2,2′-bipyridine (bipy)/SDS, which increased the rate 50-fold compared to that in pure aqueous media. The other micellar catalyst used was TX-100 and the other pro- motors used were PA and 1,10-phenanthroline (phen). The catalytic effect of SDS/TX- 100 micelle is explained.45 The oxidation of isoamyl alcohol to 3-methyl-1-butanal by ZnCr2O7 in HClO4 in 40% MeCOOH + 60% H2O is an ion–dipole reaction because the rate increased with decreasing dielectric constant of the solvent.46 The chromic acid oxidation of lysine is first order in chromate ion and less than unit order in lysine. The reaction rate increases with increasing [HClO4]. The oxidation products are Cr(III) and 5-aminopentanaldehyde. A suitable mechanism is proposed and the activation parameters are reported.47 The overall order of cetyltrimethyl ammonium dichromate (CTADC) oxidation of 2-aryl-trans-decahydroquinolin-4-ols in a MeCOOH(aq.) + 3M H2SO4 mixture is 2. The reaction indicates that axial alcohols are oxidized much faster than equatorial alcohols. Alcohols with a Me group at position 3 of the decalin ring system are also oxidized faster compared to the oxidation by other metal ions. Substituents on the Ph ring at position 2 of the decalin ring influence the oxidation.48 Nicotinium dichromate (NDC) oxidation of mandelic acid in 20% MeCOOH(aq.) + H2SO4 has been studied. The reaction is catalysed by the H+ ion.49 The pyridinium dichromate (PDC) oxidation of aliphatic alcohols to the corresponding aldehydes in the presence of p-toluene sulfonic acid (TsOH) in nonaqueous medium is first order in PDC, alcohols, and TsOH. The rate increase with TsOH indicated that the protonated PDC is the reactive species. The reaction rate increased with decreasing dielectric constant. The negative ΔS‡ is indicative of the formation of a dichromate ester prior to the rate-determining step, which involves an intramolecular proton transfer.50 Similar results are reported for analogous oxidations of cyclohexanol51 and p-benzyl alcohols.52 The protonated PDC is the active oxidant species in the oxidation of oxalic acid (oxa) in HClO4. The formation of a cyclic complex, which undergoes C–C fission in the rate-determining step, between PDCand oxa is suggested.53 Benzimidazolium fluorochromate (BIFC) oxidation of 4-oxo-4-phenylbutanoic acid + (4-oxo) in MeCOOH(aq.), HClO4, and (COOH)2 is first order in BIFC, 4-oxo, and H ion. The reaction rate increased remarkably with increasing proportion of MeCOOH in the solvent medium.54 The BIFC oxidation of pyridine-2-aldehyde (2-PyA) in 118 Organic Reaction Mechanisms 2015

+ MeCOOH + H2O to pyridine-2-carboxylic acid is first order in BIFC, 2-PyA, and H ion. The rate is favored in low dielectric constant of the medium.55 Piperidinium chlorochromate (PipCC) oxidation of glycolic acid in MeCOOH(aq.) is first order in PipCC and glycolic acid, and fractional order in H+ ion. The reaction rate is retarded with increasing dielectric constant of the medium.56 The co-oxidation of isopropanol (ipa) with EDTA by pyridinium fluorochromate (PFC) in HClO4 is 10 times greater than the total rates of individual PFC oxidations of ipa and EDTA. The oxidation of ipa is catalysed by EDT.57 The similar co-oxidation of ipa with oxa is catalysed by oxa and shows Michaelis–Menten kinetics. The rate of co-oxidation of ipa with oxa is 100 times greater than the combined individual rates of oxidation of ipa and oxa. The reaction rate is retarded with increasing dielectric constant of the medium. PFC acts as a two-electron oxidant in both oxidations.58 The kinetics of oxidation of substituted nitrones by PFC to benzaldehyde and nitrosobenzene in aqueous acetonitrile is first order in both PFC and nitrone and fractional order in H+ ions. The rate of reaction is increased by electron-releasing substituents and retarded by electron-withdrawing substituents.59 Quinolinium chlorochromate (QCC) oxidations of anline60 and phenol61 in MeCOOH(aq.) are first order in QCC, aniline, and phenol and catalysed by H+ ion + (kobs = a + b[H ]). The decrease in rate with increasing dielectric constant of the solvent is indicative of an ion–dipole interaction. The retardation in the rate by added Mn2+ ions is surmised to indicate the involvement of a two-electron transfer process. Tetraethylammonium chlorochromate (TEACC) oxidation of methionine (Met) to the corresponding sulfoxide in DMSO is first order in TEACC and Met. The H+-catalysed + reaction has the form kobs = a + b [H ]. The solvent effect is analysed using Kamlet’s multiparametric equation. A correlation of data with the Kamlet–Taft solvatochromic parameters (𝛼𝛼, 𝛽𝛽, 𝜋𝜋*) suggests that specific solute–solvent interactions play a major role in governing the reactivity.62 The oxidation of 3,4,5-trimethoxy benzaldehyde (TMBA), benzaldehyde, and dimethylamino benzaldehyde in N,N-DMF by tetraethylammonium bromochromate (TEABC) to the corresponding acids is first order in TEABC and the aldehydes. The reaction is catalysed by p-TsOH, and the rate dependence has the form kobs = a + b [H+]. The effect of the dielectric constant of the medium indicates the reaction to be of the ion–dipole type. The high rate of oxidation of N,N-dimethylamino benzaldehyde is explained. Various thermodynamic parameters for the oxidation are reported and discussed along with the validity of an isokinetic relationship. A mechanism involving the formation of a chromate ester intermediate in the slow step is proposed.63 The rate of pyridinium bromo chromate (PBC) oxidation of amyl alcohol (amyl) to amyl aldehyde in 50% MeCOOH (aq.) and HClO4 is first order in PBC and amyl and is independent of the H+ ion. The reaction rate increases with decrease in the dielectric constant of the solvent, suggesting an ion–dipole interaction.64 The catalytic activity of PA in tripropylammonium fluorochromateTPAFC ( ) oxidation of 4-oxo-4-phenylbutanoic acid (4-oxo) to benzoic acid in 50% MeCOOH(aq.) is reported. The reaction is first order in TPAFC, 4-oxo, and H+ ion.65 Similar results are reported for the oxidation of glycolic, lactic, and mandelic acids to the corresponding oxo acids under analogous conditions.66 3 Oxidation and Reduction 119

The Mn2+-catalysed periodate oxidation of p-anisidine in acetone–water medium to 4-methoxy-1,2-benzoquinone is first order each in the reactants and catalyst. An ion–dipole-type interaction is suggested by the decrease in rate with decrease in the dielectric constant of the medium. The rate–pH profile shows a maximum at pHof 7.0, which is considered to suggest the involvement of at least three different reactive species, for which a complex rate equation has been proposed.67 The Mn(AcO)3-catalysed peroxidation of styrenes in acetonitrile to [1,2-bis(t-butyl peroxy)-ethyl]benzene using t-butyl hydroperoxide as the oxidant is described. The Mn compounds in the oxidation states 2, 4, and 7 also catalyse this reaction. The target [1,2-bis(t-butylperoxy)ethyl] arenes are synthesized in yields from 46% to 75%.68 The Mn2(SO4)3 oxidation of tricyclic antidepressants (TCA) is studied in the presence of a large excess of the oxidant and MnSO4 in acidic media. The oxidative degradation of dibenz[b,f ]azepines (one class of TCA) results in the formation of substituted acri- dine with the same substituent. The reaction with 10,11-dihydro-5H-dibenz[b,f ]azepines (another class of TCA) results in oxidative dehydrogenation, which proceeds via the formation of a free organic radical intermediate. The radical, being unstable in the aqueous solution, changes to another intermediate (a non-radical dimer) in the next slower step. Further oxidation of the dimer leads to a positively charged radical dimer as the final + product. The kobs values are dependent on [H ] but independent of [TCA] within the excess concentration range of the Mn2(SO4)3 used in the isolation method. In the presence of excess of TCA, the observed rate constants are independent of [Mn(III)] and [H+] and increased slightly with increasing [TCA].69 The feasibility for 3 + 2-cycloaddition reactions is carried out using 4-fluorophenyla- zocarboxylate and N-4-chlorobenzylidene glycinate in acetonitrile with 1,8- diazabicyclo[5.4.0] undec-7-ene (DBU) as an additive and manganese dioxide as the oxidant in the presence of trifluoroacetic acid, which is added to facilitate the cleavage of the t-butyloxycarbonyl (Boc) group on the heterocyclic core. This cycloaddition protocol has been applied to form several phenylazocarboxylates and a variety of highly substituted 1,2,4-triazoles.70 The permanganate oxidation of 3-ethoxy-4-hydroxybenzaldehyde in H2SO4(aq.) is first order in the oxidant, substrate,2 andH SO4. The study reports the effect of different salts on the reaction rate.71 Similar oxidations of asparagine, glutamine, and phenylalanine are first order with respect to each reactant. Significant effects+ oftheH ion and ionic strength on reaction rate are observed, and the catalytic effects of Br− and Fe2+ ion have been examined in detail.72 Permanganate oxidation of ofloxacin to 7-amino − quinolone and Mn(II) is first order in 4MnO and fractional order in the substrate and + − 73 H ion; the stoichiometry ratio is 2:5 (MnO4 /ofloxacin). The salt effect has been studied for a similar oxidation of 4-aminoacetophenone, which is first order each in oxidant, substrate, and [H+].74 − Oxidation of 2,4-dimethoxybenzaldehyde by MnO4 ion in H2SO4 is first order each in oxidant, substrate, and H2SO4. The effect of different salts has been studied and a suitable mechanism suggested.75 Cetyltrimethylammonium permanganate (CTAP) oxidizes carbamazepine (CAS number: 298-46-4) in dichloromethane to 1H-dibenzo[b,f]azepine-4,5-dione. The reaction is first order in CTAP and fractional order in carbamazepine. Ionic surfactants catalyse the 120 Organic Reaction Mechanisms 2015 reaction as a result of the formation of mixed reverse micellar aggregates with CTAP. The proposed mechanism consist of a first rate-determining syn addition of permanganate to the C=C bond of carbamazepine to form a Mn(V)–ester intermediate through a non-polar cyclic TS. Subsequently, the intermediate decomposes and hydrolyses in fast steps to the dicarbonyl product.76 A highly efficient method has been developed for the oxidation of a wide varietyof alcohols (benzylic, allylic, propargylic, and aliphatic) to the corresponding aldehydes or ketones in high yields (up to 99%); it involves a catalyst generated in situ from Mn(OTf)2 and the ligand (6) taken in 1:1 ratio, with H2O2 as the oxidant in presence of a carboxylic acid in acetonitrile. Hammett analysis confirmed that the active oxidant is electrophilic.77

N N H H

N N O O Bus Bus (6)

DFT calculations have resolved the mechanistic controversies in the Ni(OTF)2- catalysed oxidative C(sp2)–H/C(sp3)–H coupling of benzamides with toluene derivatives using i-C3F7I as a mild oxidant in the presence of PPh3 and Na2CO3. The calculations exclude the two previously proposed mechanisms and instead favour a more feasible iodine atom transfer (IAT) between i-C3F7I and the Ni(II) intermediate. Consistent with this mechanism is the presence of a carbon radical and the experimental observation that the reaction is completely quenched by TEMPO. Meanwhile, the hydrogen atom abstraction of toluene is irreversible and the activation of the C(sp2)–H bond of benzamides is reversible. Both these conclusions are in good agreement with previously investigated deuterium-labeling experiments.78 The coupling of aryl acids with unactivated alkyl bromides, catalysed by Ni(acac)2 in combination with 4-t-butyl-2-(4-t-butylpyridin-2-yl) pyridine/DMF in the presence of MgCl2 and Boc2O in CH3CN/DMF, has been reported to generate the ketone in 88% yields. Even though the loading of the catalyst and acid is significantly reduced, compared to the amount of the air-sensitive catalyst Ni(Cod)2 (Cod = cyclooctadiene) used previously for the coupling of alkyl iodides with aryl acids, this represents a significant increase in efficiency and is more practical for the synthesis of secondary alkyl aryl ketones. Synthesis of aroyl C-glycosides by direct reductive coupling of 1-glycosyl bromides with acid derivatives provided rapid access to the construction of C–C bonds on carbohydrates. This method may be useful for the synthesis of bio-actively relevant compounds.79 NiBr2(DME) in association with (R)-Me-Duphos (7) in the presence of HCOOH (H2 source) and Et3N (base) acts as the catalyst in the asymmetric transfer hydrogenation of electron-deficient olefins giving 92% yield with 91% ee in the model 3 Oxidation and Reduction 121 reaction. Deuterium-labelling experiments indicate a major pathway involving formate decarboxylation, asymmetric hydride insertion into olefins, and protonation of the 80 resulting Ni enolates. ee

Me Me

P P

Me Me (7)

A highly enantioselective [Ni(Cod)2]-catalysed reductive cyclization of alkynones is achieved in doxane using (S)-AntPhos (8) or BI-DIME (9) and triethylsilane as the ligand and the reducing reagent, respectively. A broad range of chiral tertiary allylic alcohols with various alkyl/aryl substituents bearing furan/pyran rings are synthesized with almost perfect enantioselectivity (99% ee) and yield (98%). This reaction has a broad substrate scope and enabled the efficient synthesis of the lignin dehydroxycube- bin and chiral dibenzocyclooctadiene skeletons. Mechanistic studies demonstrated that the cyclization is catalysed by a Ni catalyst with a single chiral monophosphine ligand. 81 A simple model has been proposed to rationalize the stereochemical outcome. ee O O

P P But But MeO OMe

(8) (9)

A method to directly transform both aromatic and aliphatic aldehydes into esters or amides is developed that uses Ni(Cod)2 as the catalyst and 𝛼𝛼,𝛼𝛼,𝛼𝛼-trifluoroacetophenone (PhCOCF3) as the oxidant in the presence of NHC (N-heterocyclic carbine) ligands in 1,4-dioxane. Aldehydes act both as the substrate and hydrogen acceptor. Both ben- zophenone and PhCOCF3 show a remarkable enhancement in rate and selectivity for the ester. Related oxidations typically require excess alcohol, or alcohol as the solvent. Mechanistic data that supports a catalytic cycle involving oxidative addition into the aldehyde C–H bond is presented.82 [NiCl2(dme)] (dme = 1,2-dimethoxyethane) catalyses the asymmetric transfer hydrogenation of hydrazones and other ketimines with formic acid in the presence of the ligand (S)-binapine and EtOH and affords the product with 97% ee and full conversion. HCOOH and EtOH act as hydrogen surrogates. In alcoholic solvents the reaction is much faster than in aprotic solvents. DFT study suggests that the nickel/binapine catalyst uses 122 Organic Reaction Mechanisms 2015 shape complementary and weak attractive interactions to effect asymmetric induction, 83 instead of conventional steric repulsion. ee An air- and moisture-stable Ni(II)(IPr)(g1-Cp)(g5-Cp) complex (10), which acts as an effective precursor for generating catalytically active Ni(0) species, proved to be an effective pre-catalyst for the dehydrogenative silylation of various aryl and alkyl alcohols with hydrosilanes (HSiEt3) in toluene, giving the corresponding silyl ethers in 59–99% isolated yields. Time course studies revealed that the reaction has an induction period, during which the Ni(II) complex gets reduced to catalytically active Ni(0) species.84

Pri Pri

N N

Pri Pri Ni

(10)

Copper, Silver, Gold, and Thallium The kinetics of oxidation of myo-inositol (INOS) by diperiodatocuprate(III) (DPC) in alkaline medium is first order in DPC and less than unit order in INOS. The rate − − increases with the OH ion concentration. The rate decreases with increase in IO4 ion and ionic strength and with decrease in the dielectric constant of the medium. The activation parameters with respect to the slow step of the mechanism are determined.85 The oxidation of captopril (a sulfur-containing drug) by alkaline DPC to captopril disulfide as major product, with trace amount of l-proline, is first order eachin DPC − − and captopril. The rate is retarded with increasing OH and IO4 concentration. The reaction constants of the various steps of the mechanism were evaluated and used to regenerate experimental first-order rate constants for various experimental conditions.86 The alkaline oxidation of butylamine and isobutylamine by DPC is pseudo-first-order − in DPC and 1 < nap < 2 in the reductants. kobs decreases with increase in [IO4 ] and [OH−]. The reaction exhibits a negative salt effect, and the rate for isobutylamine exceeds that for butylamine.87 ′ The [Cu(CH3CN)4]PF6/ligand N,N -di-t-butyl-ethylenediamine system with dimethylaminopyridine or N-methylimidazole additives in CH2Cl2 is the catalyst for aerobic oxidation of primary and secondary alcohols (R1CHOHR2,R1,R2 = alkyl, allyl, aryl, and heteroaryl) without an external N-oxide co-oxidant. This system works without TEMPO at ambient pressure and temperature, and displays a unique reactivity for the synthesis of aliphatic ketones from non-activated secondary alcohols (secondary alcohols are challenging substrates for catalytic aerobic systems).88 Computational calculations have been applied to investigate the mechanism of trifluoromethylation of iodobenzene with well-defined N-heterocyclic carbene-supported 3 Oxidation and Reduction 123

CuI trifluoromethyl complexes. Four proposed reaction pathways, namely (a) 𝜎𝜎-bond metathesis, (b) concerted oxidative addition–reductive elimination (OARE), (c) iodine atom transfer, and (d) single-electron transfer, were computed by DFT. The results indicate that the OARE mechainism is the favoured one and that the trifluoromethylation may involve concerted Ar–X oxidative addition to the Cu(I) centre as the rate-determining step.89 Azabicyclo[3.1.0]hexane derivatives have been synthesized by direct oxidative coupling of arylmethyl ketones and maleimides in the presence of a copper catalyst CuI/bipy or 4,4′-t-butyl-bipy, and di-t-butyl peroxide as the oxidant in chlorobenzene; the best yield was 72% at 110 ∘C. The dehydrogenative annulation involves a double 90 C–H bond functionalization at the 𝛼𝛼-position of the ketone. An efficient CuI-catalysed C(sp3)–H oxidative cross-coupling of propiophenones with acetophenones in DMSO and in presence of AcOH with molecular oxygen as the oxidant has been developed. The addition of the radical scavenger TEMPO shuts down the reaction completely, indicating that a radical pathway might be involved. The desired products are obtained in high yields from the reactions of propiophenones with 2-oxo- 2-arylacetic acids, which were produced from the oxidation of acetophenones.91 An aerobic CuI-catalysed intramolecular dehydrogenative amidation of unreactive C(sp3)–H bonds of aliphatic acid derivatives in a mixture of benzonitrile-o-xylene (3:2) ∘ in the presence of Na2CO3 at 140 C using O2 as the oxidant has been reported to give yields up to 98%.92 An efficient one-step CuCl-catalysed intramolecular alkoxylation of purine nucleosides in DMF with di-t-butyl peroxide (DTBP) as the oxidant results in the synthesis of 5′-O,8-cyclopurine nucleosides in yields up to 90%. The reaction proceeds well 93 even in the gram scale. A study of the substrate scope in CuCl2-catalysed and chloroacetate-promoted selective oxidation of heterobenzylic methylenes with molecular O2 (oxidant) shows that various N-heterocyclic compounds are converted into the corresponding ketones with high selectivity and good to excellent yields. The N-heterocyclic compounds and ethyl chloroacetate work synergistically to activate C–H bonds in the methylene group, which results in the easy generation of free-radical intermediates, thus leading to the corresponding ketones in good yields.94 The oxidative dealkylation of 2,4,6-tri-t-butylphenol with O2 catalysed by Cu(II) complexes of the N-octylated bisbenzimidazolyl ligand is pseudo-first-order in the catalyst and the substrate; a reactive Cu(II)-dioxygen species carries out the oxidation to 2,6-di t-butylbenzoquinone and 4,6-di-t-butylbenzoquinone via a phenoxyl radical species. The p-quinone is formed threefold faster than the o-quinone, and a possible alternate pathway for the former is supported by the isolation of an intermediate 4,4′-peroxybis(2,4,6- tri-t-butyl)cyclohexa-2,5-dienone species and its structural characterization. Externally added acetate anion increases the rate of reaction by 22 times, which is attributed to the larger concentration of the phenoxyl radical formed.95 An efficient oxidative coupling reaction of benzylic compounds and 1,3-dicarbonyls with O2 is catalysed by DDQ and NaNO2 in the presence of HCOOH acid and MeNO2 as solvent. The system shows high efficiency and the coupling products are obtained in good to excellent yields.96 2+ 2− The Cu -ion-catalysed and un-catalysed [PtCl6] oxidation of l-asparagine (Asn) + to 𝛼𝛼-formyl acetamide, NH4 ion, and CO2 in aqueous H2SO4 medium are first order 124 Organic Reaction Mechanisms 2015 in oxidant and less than unit order in H+ ion. The order in Asn decreases from 1 in the 2 un-catalysed path to <1 in the catalysed one. The catalysed path is first order in Cu + ion. Increasing the ionic strength and dielectric constant decreases the oxidation rates.97 A variety of 2-benzylindoles have been obtained directly, in moderate to good yields, by Cu(OAc)2-catalysed regioselective cross-dehydrogenative coupling (CDC) of N-(2- pyrimidyl)-indoles with arylmethanes using DTBP as oxidant and benzaldehyde as an effective additive at 120 ∘C.98 A catalyst generated in situ from the system Cu(OAc)2⋅H2O/chiral (R)-BINAP/ polymethyl hydrosiloxane has been investigated for the asymmetric reduction of aromatic ketones to (R)-1-aryl ethanols in up to 99% yield and 93% ee in air atmosphere in the presence of a MeOH/NaOH mixture. The electronic effect and steric hindrance of the substituents on the aromatic ring have an interesting influence on both the yields and enantioselectivities of the asymmetric hydrosilylation, for which a mechanism has been proposed.99 The Cu(OAc)2⋅H2O-catalysed enantioselective oxygen atom transfer from racemic Davis’ oxaziridine (11) to N-Boc-3-phenyl-2-oxindole (12) in Et2O in the presence of (13) provides 3-aryl-3-hydroxy-2-oxindole derivatives (14) with moderate enantioselectivity (96% ee) and 85% yield. X-ray crystallographic analysis of the isolated Cu(II) complex reveals its N,N,O-tri dentate coordination, which enables effective catalytic 100 activity. ee Ts N H O

N (11)

+ N

Me OH HO

O O N N Me Boc Boc

(12) (13) (14)

A Cu(OAc)2-catalysed oxidative esterification of ortho-formyl phenols with RCHO (R = aromatic or aliphatic) using aqueous TBHP as oxidant yields esters in moderate to good yields. The labile formyl group remains intact under oxidative conditions and can be further transformed into various useful products. The environmentally friendly 3 Oxidation and Reduction 125 benzylic alcohols are suitable substitutes for aldehydes in the reaction. The method provides an alternative protocol for classical esterification reactions.101 Cu(OAc)2 is the catalyst of choice in the presence of the oxidant DTBP and KI as additive in the cross-dehydrogenative coupling reactions of coumarins with cyclic ethers and cycloalkanes, affording a variety of C(3) functionalized coumarins bearing the C(sp2)–C(sp3) bond in moderate to excellent yields (80%). 6-Methyl coumarin reacts with all of the tested cycloalkanes to form products with excellent yields. The conversion is proposed to proceed via a radical process.102 Investigation of Cu(OAc)2-catalysed C–C bond cleavage of primary propargyl alcohols, in presence of the radical scavanger TEMPO, additive morpholine, and O2 as oxidant, has established that hemiaminal intermediates result from the nucleophilic addition of amines to the initially formed aldehydes. Hemiaminals are known to undergo both 𝛽𝛽-hydrogen elimination and the C–N bond cleavage; however, in this case the less polar C–C bond is cleaved to generate the alkyne–copper intermediate and the N-formyl amine. The addition of azides to the reaction mixture demonstrated good dealkynylation conversion efficiencies for aromatic, aliphatic, and silyl-substituted propargyl alcohols.103 The Cu(OAc)2-catalysed direct alkynylation of un-activated (hetero)aryl C–H bonds in (15) with TIPS-alkynes (16)(TIPS = triisopropylsilyl) in the presence of Ag2CO3 and bases Et3N and Na2CO3 in dioxane produces the desired alkyne (17) under aerobic conditions (Scheme 1). Deprotonation of the terminal alkyne is facilitated by Et3N. The maximum yield of (17) under specific optimized condition is 90%. The directing PIP group (18), derived from 2-(pyridine-2-yl)isopropylamine, is removed under mild conditions. The TIPS group, essential for the protocol, is easily removed by the treatment with tetra-n-butylammonium fluoride to produce the terminal alkyne, which serves asa versatile handle for further synthetic elaboration.104

O O TIPS PIP PIP N N + PIP H H = N H H (15) (16) (17) TIPS (18)

Scheme 1

The CuBr-catalysed cascade sp3 C–H bond oxidative functionalization of 2-ethylazaarenes in DMF and isonitrile with persulfate ion as oxidant has been developed. The two different sp3 C–H bonds in 2-ethylazaarenes are selectively oxidized and four new types of bonds (=C=O, C=N, C–C, C–O) are constructed in one operation. Starting from simple substrates and nitro source, this reaction provides an efficient approach to produce new kinds of isoxazolines.105 A CuBr2-catalysed CDC of N-arylacrylamides with chloroform using t-butylperoxy- benzoate (TBPB) as oxidant gives trichloromethylated oxindoles in 87% yield and 126 Organic Reaction Mechanisms 2015

regioselectivity. This reaction should proceed by the cascade addition of ⋅CCl3 radicals, C=C addition, and aryl cyclization.106 A CuCl-catalysed oxidative coupling of ethers and salicylaldehydes with TBHP as the oxidant forms a diverse library of acetals in 92% yield without affecting the adjacent sensitive formyl group, which remains intact under experimental conditions. The reaction occurs without a ligand or an additive, and proceeds through a radical pathway.107 An efficient CuBr-catalysed aerobic oxidative dicarbonylation of indoles in toluene (solvent) and pyridine (base) using 𝛼𝛼-carbonyl aldehydes affords various C(3) indole- substituted 1,2-diketones in good to excellent yields.108 The Cu2O-catalysed cycloalkylation–peroxidation strategy is developed via a three- component reaction involving cycloalkanes, TBHP, and internal conjugated alkenes possessing electron-withdrawing groups (EWGs). This process installs C–O and C–C bonds via sp3 C–H functionalization with concomitant generation of two stereocentres. This regioselective radical addition to a coumarin system is opposite to that of styrene. Treatment of 3-acetylcoumarin with TBHP in decane catalysed by Cu2O and in the presence of cyclohexane gives the best yield (60%) of the product.109 The possibility of the formation of the bis-𝜇𝜇-oxido dicopper intermediate in the O2 oxidation of Cu(I)-PPN (PPN = 2-(diethylaminoethyl)-6-phenylpyridine) and subsequent hydroxylation of the pendant phenyl group is investigated by studying the similar oxidation of the Cu(I)–BDED complex (BDED = N′-benzylidene-N,N- diethylethylenediamine), which has the same basic structural features and is oxidized to salicylaldehyde in good yields. The underlying reaction mechanism for the PPN complex is studied by DFT, and the results for representative stationary points along reaction paths of the BDED complex reveal a closely related mechanistic scenario. The results demonstrate a new, facile synthetic way to introduce OH groups into aromatic aldehydes.110 Copper(I) complexes of tripodal ligands (19)–(21), featuring three different N-heterocyclic donor units, not only act as catalysts for the oxidation of NaDTBP (sodium 2,4-di-t-butylphenolate) with O2 to give mainly the corresponding catecholate and quinone (Q) but also cleave the resulting catecholate in a dioxygenation reaction. The copper species responsible for the monooxygenation is initially formed from 19OTf/ − NaDTBP/O2 (OTf = CF3SO3 ). The copper species responsible for dioxygenation

Me Me Me Me Me N N N Me NN Me Me N O O O Me Me N Me N NN NN Me N

(19) (20) (21) 3 Oxidation and Reduction 127 is formed thereafter and consumes Q as substrate. Hence, the complexes show not only monooxygenase but also dioxygenase activity, thereby mimicing product formation by two enzymes.111 3 + 2-Cycloaddition/oxidation of organic azides with nitro-olefins, catalysed by Cu(OTf)2, in DMF/AcOH and oxidized by air, affords NO2-substituted 1,2,3-triazoles with high regioselectivity in good to excellent yields. The reaction involves the loss of two hydrogens instead of HNO2 for nitro-olefins and tolerates a broad range of functional groups. The potential viability and generality of this reaction for the construction of various 4-amino 1,2,3-triazoles may be anticipated (reduction of the NO2); derivatives such as 4-amino 1,2,3-triazoles are already known to increase potency as antibacterial agents.112 The synthesis of a broad range of quinolones promoted by the Lewis acid Cu(OTf)2, which acts as oxidant, is achieved in a single step by reacting various benzylic azides with internal alkynes under neutral reaction conditions in MeNO2. The protocol, which has a broad substrate scope with improved yields and excellent regioselectivities, has been applied to the synthesis of biologically active 6-chloro-2,3-dimethyl-4- phenylquinoline (antiparasitic agent) and 3,4-diphenyl quinolin-2(1H)-one (p38𝛼𝛼MAP kinase inhibitor). A plausible reaction mechanism involves rearrangement of benzylic azide to N-arylimine (Schmidt reaction) followed by intermolecular 4 + 2-cycloaddition with internal alkynes.113 The kinetics of Ag(I)-catalysed oxidation of phenethyl alcohol by PDP (PDP = peroxodiphosphate) in aqueous HNO3 is first order in PDP and fractional order in Ag(I). The rates, which increase in the order –NO2 < –Cl < –H< –CH3 < –OCH3 of para-substituted phenethyl alcohols, follow a Hammett correlation. The correlation between enthalpies and free energies of activation is reasonably linear with an isokinetic temperature in the range 425–432 K. Ea increases with the substitution of EWGs but decreases when electron-releasing groups are substituted on the benzene ring.114 The kinetics of Ag(I)-catalysed oxidation of l-ascorbic acid (H2A) by PDP in acetate buffers are independent of the substrate concentration. A plausible catalytic redox cycle involving Ag(I)/Ag(II) has been suggested; the presence of Ag(II) is confirmed by the ′ addition of 2,2 -bipyridyl when a brown-orange color of the Ag(bipy)2 complex of transient life time is observed.115 Oxidative alkenylation of benzamides and acetanilide with ethyl acrylate, catalysed by the Cp*Co(CO)I2 complex (M), is reported to access the desired product in up to 93% yield using AgOAc as the oxidant in the presence of AgSbF6 as the additive and 116 ClCH2CH2Cl as the solvent (Cp* = pentamethylcyclopentadienyl). The oxidation of l-asparagine (Asn) by bis(hydrogenperiodato)Ag3+ ion 5− 3+ ([Ag(HIO6)2] ) in aqueous alkaline media is first order in Ag and Asn. The − second-order rate constants k2 increase with OH but decrease with increasing − [IO4 ]tot. The mechanism is proposed to feature two pre-equilibria, which lead to 3− an intermediate complex [Ag(HIO6)(Asn)(OH)] that breaks down in two parallel rate-determining steps, being independent and dependent on OH−, respectively.117 Correlation between structure and reactivity is studied in the oxidation of substituted benzyl alcohols to corresponding benzaldehydes by tetrakis(pyridine) silver dichromate (TPSD) in DMSO. The effect of the solvent is analysed using Taft and Swain’s 128 Organic Reaction Mechanisms 2015 multiparametric equations.118 The results of a combined DFT and experimental study of the mechanism of Ag2CO3-catalysed isocyanide–alkyne cycloaddition in dioxane (solvent) indicate that it is a multi-catalysed radical process. The catalyst serves as a base for the deprotonation of isocyanide and as oxidant to initiate the initial formation of the isocyanide radical. Isocyanide and dioxane regenerate the radical for the next catalytic cycle after the cycloaddition between the isocyanide radical and silver acetylide and simultaneously complete the protonation. The solvent dramatically improves the reaction activity by stabilizing the transition-state structures via Ag···O coordinations and C–H···O hydrogen bonds in Ag-containing processes as well as a much more efficient H-shift than in the substrate/water-assisted and direct119 cases. The oxidation of vitamin B6 (pyridoxine hydrochloride) by diperiodatoargentate(III) (DPA) to pyridoxinal in aqueous alkaline medium is first order in DPA, whereas the − order with respect to vitamin B6 and OH ion changes from first order to zero order as − the concentrations of vitamin B6 and OH ion are increased. A mechanism involving 120 complex formation between DPA and vitamin B6 is proposed. The oxidation of vitamin B6 by DPA, catalysed by Ru(III), in alkaline medium is first order in DPA and the apparent order in vitamin B6, Ru(III), and OH− ion is less than unity. The first order changes to zero order as the concentrations of vitamin B6and OH− are increased. The reaction in alkaline medium proceeds via a Ru(III)–vitamin B6 complex, which further reacts with 1 mol of DPA in the rate-determining step to give the product.121 A new synthetic route to medium-sized azepine and benzazepine derivatives, in yields up to 98%, involves highly regio- and chemo-selective oxidative ring expansion of 2-alkynyl-1,2-dihydropyridines or -quinolines by using pyridine-N-oxide as the oxidant ∘ and PPh3AuNTf2 as the catalyst in toluene at 50 C. The ring expansion proceeds through exclusive 1,2-migration of a vinylic group (C–C bond) without competing 1,2-H and 1,2-N migration. DFT studies indicate that the reaction proceeds through the formation of a cyclopropyl gold intermediate, and no gold carbene species is involved.122 3-Coumaranones have been synthesized by the oxidation of o-ethynylanisoles with 8- isopropyl quinoline N-oxide in methanesulfonic acid (MsOH) using BrettPhosAuNTf2, (NTf2 = bis(trifluoromethylsulfonyl)amide) (22) as the catalyst in 1,2-dichloroethane (DCE) at room temperature. An isolated product yield of 86% is attained by maintaining

OMe

MeO AuNTf2 Me P Cy Cy Me Me

Me Me (22) 3 Oxidation and Reduction 129 the oxidant in slight excess of MsOH. The method was used to synthesize the natural product sulfuretin. A plausible mechanism for the reaction is consistent with results of a DFT study.123 + The possibility that cationic gem-diaurated complexes [(Ph3P)2Au2Ph] (A), [(Ph2P)2 + + CH2)Au2Ph] (B), and [(Ph2PCH2)2)Au2Ph] (C) can themselves directly facilitate C–C bond-forming reactions with allyl halides CH2=CHCH2X (X = Cl, Br, and I) in the gas phase has been examined. The significant finding is that the ligand plays apiv- otal role in promoting C–C bond coupling: that is, while (A) does not undergo C–C bond coupling with the allyl halides, (B) does and (C) reacts only with allyl iodide. DFT calculations have been applied to examine the potential mechanism for C–C bond coupling reactions of (B) with each of the three allyl halides.124 t The Me4Bu XPhosAuCl-catalysed selective oxidation of 4-oxahepta-1,6-diynes with 2,6-dichloropyridine 1-oxide in DCE in presence of the additive NaBARF4 proceeded smoothly at room temperature to give the corresponding 2H-pyran-3(6H)-ones (23), chromen-3(4H)-ones (24), and further product (25) via the 𝛽𝛽-gold vinyl cation intermediate, which can be trapped by an external N-oxide and internal aryl ring system.125

O R O O O R Me O R′ O O Me (23) (24) (25)

The oxidation kinetics of paracetamol by Tl(III) in acid perchlorate medium are first order in Tl(III), and is of complex dependence on paracetamol and inverse complex dependence on H ion.126 Quantum-mechanical (QM) calculations demonstrate that Tl(TFA)3 (TFA = trifluoroacetic acid) oxidizes alkanes via a closed-shell C–H activation mechanism and a metal- alkyl (MR) intermediate functionalization mechanism. The calculations also reveal that the low-spin ground state of Tl(III) determines the preference for a closed shell over an open shell C–H bond oxidation mechanism in Co(TFA)3 oxidation. A comparison of low-spin Ir(TFA)3 and Tl(TFA)3 for C–H activation and MR functionalization reveals that the key to the direct oxidation of alkanes by Tl(III) is a moderate barrier for C–H bond activation that is lower than open-shell pathways, coupled with a very low barrier for MR functionalization. The QM/(DFT) calculations provide a reactivity model for why Tl(TFA)3 promotes alkane C–H bond activation but Hg(TFA)2 does not. The calculations also show that Tl(TFA)3 is advantageous over d-block metal trifluoroacetate compounds as a result of a fast MR functionalization step.127

Cerium, Samarium, Titanium, Cobalt, Vanadium, Tungsten, Rhenium, and Molybdenum The thermodynamic parameters for the formation of the intermediate [CeOHOx]+ (H2Ox = oxalic acid) and the kinetic parameters in the oxidation of H2Ox by Ce(IV) at 130 Organic Reaction Mechanisms 2015 pH 0.4–1.1 in sulfuric acid have been determined. The redox process occurs between 4+ − Ce (SO4)2 and Ox. The rate law and the reaction mechanism associated with the reaction have been established.128 The kinetics of Ru(III)- and Ir(III)-catalysed oxidation of p-chlorobenzaldehyde to p-chlorobenzoic acid by Ce(IV) was studied in the presence and absence of the cationic surfactant N-cetyl pyridinium chloride (CPC). The rate is much faster for catalysis by Ru(III) than by Ir(III) in micellar media. The use of Ru(III)–CPC increased the rate by up to 5000-fold compared to Ru(III) in aqueous media. The micellar effect is explained on the basis of reverse CPC micelle formation.129 Anhydrous Ce(SO4)2 in chloroform selectively converts oximes to the corresponding carbonyl compounds in good yields. The reaction is substituent-dependent with 2− the Hammett constant 𝜌𝜌 =−1.94. The SO4 anion is the source of O in the formation of the carbonyl group. It forms a sulfate ester with the N-coordinated oxime, the fragmentation of which leads to CeSO4 and the carbonyl compound. The formation of 1-(dinitromethyl)benzene is assumed to be a product of isonitroso hydrogen reaction with arylaldoximes.130 The kinetics of oxidation of the Schiff base (CHMA2BA = 5-chloro-2-hydroxy-4- methylaceto phenone-2′-bromoanil) with Ce(IV) in aqueous sulfuric acid medium are of first order in Ce(IV) and Schiff base. The formation of a complex between Ce(IV) −1 −1 and the Schiff base is indicated by a linear plot between k1 and [Schiff base] with an intercept on the rate ordinate. A possible mechanism is suggested.131 Oxidation of Schiff base and its kinetics have been studied by Ce4+/Ce3+ redox systems in aqueous sulfuric acid medium. The order of the reaction with respect to Ce(IV) −1 as well as Schiff base is 1. A plot of k1 against the inverse concentration of 5-chloro- 2-hydroxy-4-methylacetophenone-2′-bromoanil [CHMA2BA]−1 is linear with an intercept on the rate axis, which suggests the formation of an equilibrium complex between the reactants prior to the rate-determining step. The effects of different salts (KCl, NaCl, and NH4Cl), ionic strength, temperature, and solvent on the rate of reaction have also been studied. The thermodynamic parameters ΔE, ΔH, ΔG, and ΔS and the activation energy ‘A’ were also evaluated for the oxidation process, for which a possible mechanism is suggested.132 The general utility of N,N-dimethyl-2-aminoethanol (DMAE) as an additive in SmI2- based reductions is reported. It is found that the SmI2–DMAE system is capable of reducing a range of substrates including alkyl halides, ketones, lactones, and arenes. Mechanistic studies on anthracene reduction are consistent with the formation of a highly ordered TS.133 The catalyst from the cis-diaminocyclohexane (DACH)-derived salalen ligand (26) i and Ti(OPr )4 combines high activity and enantioselectivity and catalyses the asymmetric epoxidation of non-conjugated terminal olefins with aqueous2 H O2 in presence of dichloroethane. High yields and enantiomeric excesses (up to 96% ee) are obtained at ee 134 loadings as low as 0.1–0.5%, and even under solvent-free conditions. de An expeditious method for the reduction of secondary and tertiary amides to corresponding amines by LiAlH4 (LAH) in the presence of TiCl4 and Et2O has been reported to give good yields without modification of the stereochemistry of the chiral centres. The protocol is extended to the reduction of amides of N-𝛼𝛼-protected amino acid and 3 Oxidation and Reduction 131

N (R)(S) N H OH HO aR R R = c-hexyl

(26) dipeptides to the corresponding 1,2-diamines and diaminoalcohols in high yields and with retention of configuration at the chiral centres.135 A study of dehydrogenation of dimethylamine borane using different titanocene(III) 2 complexes with 2-phosphinoaryloxide ligands is presented. Complexes Cp2Ti(𝜅𝜅 -O, 5 1 P–O–C6H4–PR2) (Cp = 𝜂𝜂 -cyclopentadienyl) and Cp*2Ti(𝜅𝜅 -O–O–C6H4–PR2) 5 (Cp* = 𝜂𝜂 -pentamethylcyclopentadienyl) are prepared by reactions of the 2- phosphinophenol ligand with different titanocene sources and fully characterized. Their catalytic activity depends on the steric influence of the cyclopentadienyl ligand, on the coordination mode of the 2-phosphinoaryloxide ligand, and on the solvent used. EPR studies elucidated the fate of the Ti(III) catalyst.136 The kinetics of Co2+-catalysed oxidation of acetamide by the sodium salt of N-bromo-p-toluenesulfonamide (BAT) in aqueous medium is first order each in BAT and acetamide. The dependence on Co2+ is given by k = 1.0 × 10−3 + 6.50 [Co2+]. The oxidation products are AcOH, p-toluenesulfonamide, and nitrogen.137 The oxidation of 1-methyl-2-thiourea (MTU) by [(NH3)5Co(O2)Co(NH3)5]Cl5⋅H2O, 5+ abbreviated as Co(O2)Co , in aqueous HClO4 has the empirical rate law −d[Co 5+ 5+ −2 3 −1 −1 (O2)Co ]/dt = k2[Co(O2)Co ] [MTU] with k2 = (2.65 ± 0.15) × 10 dm mol s at 31.0 ± 1.0 ∘C. The products are the corresponding urea derivative, molecular oxygen, and Co(II). The reaction is catalysed by the added anions, and the rate increases with increase in the ionic strength of the reaction medium.138 An efficient Co(OAc)2-catalysed intramolecular C–O bond formation has been achieved via cross-CDC of acids with an (sp3)C–H bond, using oxygen as the terminal oxidant. The protocol requires the use of MeCN as the solvent and (d,l)-tyrosine as the additive to achieve a 90% yield at room temperature. This strategy allows convenient access to a series of ring-fused dihydro-benzoxazinones and its derivatives.139 The hydroboration of terminal alkynes with HBPin (Pin = pinacolate), catalysed by the Co catalyst (27), results in vinylboronate esters in high yield and (Z) selectivity. A mechanism, based on isotopic labelling and stoichiometric studies as well as the isolation of the intermediates, supports the selective insertion of an alkynylboronate ester into a Co–H bond. The identity of the imine substituents dictates the relative rates of activation of the Co pre-catalyst with HBPin or the terminal alkyne and is responsible for the stereochemical outcome of the catalytic reaction.140 132 Organic Reaction Mechanisms 2015

Me • Me N N Co N Cy Me (27)

The combination of Co(BF4)2⋅6H2O with a tridentate phosphine ligand is reported to catalyse the reduction of a wide range of esters and carboxylic acids under relatively ∘ 141 mild conditions (100 C, 80 bar H2) with a TON of up to 8000. A study of the dispersion–correlation hybrid DFT on three LCo(N2)-catalysed (L = meridional bis-phosphinoboryl) reactions, namely (a) hydrogenation of styrene using H2, (b) dehydrogenation of amine-borane, and (c) transfer hydrogenation of styrene, suggests that LCo(H)2 is the active species which gets deactivated by forming a hydrido-borane cobalt tetrahydridoborate complex in the reaction involving amine-borane. The deactivation happens through an SN2-type nucleophilic attack by the LCo(H)2 on amine-borane. The rate-determining barriers for both the dehydrogenation of amine-borane (NMe2H–BH3) and the transfer hydrogenation of styrene by amine-borane are higher than that of the hydrogenation of olefin using2 H (g). The 142 active catalytic species is LCo(H)2. The hydrogenation of esters by H2 in THF in presence of NaHBEt3 and t-BuOK to the corresponding alcohols in high yield is catalysed by a PNNH-based cobalt pincer complex (28). The proposed mechanism (Scheme 2) involves enolate intermediates, thus suggesting selectivity for enolizable esters.143

t O O− Bu t-BuOK K+ N 1 1 + t-BuOK t R R Bu O R2 O R2 N Co P t H Cl Cl Bu H2 (28) (28) − O K+ R1O− K+ R2CH CHO + 2 R1 O R2

1 2 t-BuOK + R OH R CH2CH2OH

Scheme 2

Oxidations of d-xylose,144 maltose catalysed by Ag+ ion,145 and d-ribose catalysed 3+ 146 by Ir ion in HClO4 medium followed first-order dependence on substrates and on 3 Oxidation and Reduction 133 the oxidant V(V). The reaction rates increased with [H+]. The rate of xylose oxidation 3+ 2− − is increased by the Ir ion and ionic strength but retarded by SO4 and HSO4 ions. The negative values of ΔS‡ in each case are considered to be indicative of an ordered, activated complex and highly solvated TS. Vanadium(V) oxidation of o-, m-, and p-Me-substituted phenoxy acetic acid hydrazides to the corresponding aryloxy acetic acids in sulfuric acid indicated that the reaction rate decreased with the hydrazide concentration and decreasing dielectric constant but increased with the acid concentration. A complex formed between the reactants decomposes to give products via a one-electron transfer process with free- radical intervention. The negative values of the entropy of activation are considered to support the proposed mechanism.147 7− [MnV13O38] (13-vanadomanganate(IV) in acetate buffer; (pH 3.25–4.30) oxidizes 2-mercaptoethanol to 2-hydroxyethyl disulfide and is itself reduced2 toVO + in a multi-step process. The kinetics of conversion of the oxidant to an intermediate one-electron-reduced form, which is the first step of the mechanism, has been measured; the intermediate is metastable in the pH range studied and decomposes into smaller oligomers, which are further reduced to free vanadyl ions. The 13th V(V) is preferentially reduced first by one-electron reductant, whereas the caged Mn(IV) isnot reduced first. The oxidant seems kinetically more active when mono-protonated.148 The kinetics of oxidation of hydroquinone (hq) and catechol (cc) by the heteropoly V V 5− 10-tungstodivanadophosphate anion, [PV V W10O40] in aqueous acidic medium has been studied. The reactions at constant [H+] are first order in the oxidant and hq but shows Michaelis–Menten kinetics with cc. The rate is insensitive to [H+] in the pH range 1.2–1.7. The lower rates for deuterated hq and cc in D2O indicates breaking of the –OH bond in the rate-limiting step. Based on the observed kinetic isotope effect (KIE) and calculated ground-state free energy change (ΔG0) values, a hydrogen atom transfer mechanism is suggested for the reaction. The self-exchange rate constant of the oxidant (VVVIVOH/H⋅) in acetonitrile was evaluated by applying the Marcus equation.149 The H2O2 oxidation of N,N-dimethylaniline to N-oxide, catalysed by oxovanadium (IV)-salen ion, follows Michaelis–Menten kinetics, and the electron-donating groups in the substrate as well as in the salen ligand accelerate the rate. The Hammett constant 𝜌𝜌 has a negative value. The substituent effect is accounted for in terms of rate-determining bond formation between the peroxo bond of the oxidant and the N-atom of the substrate in the TS. Trichloroacetic acid (TCA) catalysed the reaction enormously. The percentage yield of the product becomes excellent in the presence of TCA.150 VO(acac)2-catalysed oxidative coupling of substituted 2-arylimidazo[1,2-a]pyridines in dioxane to N-methylmorpholine oxide, which acts both as a coupling partner and an oxidant, has resulted in yields up to 90%. Mechanistic investigations indicate that the reaction may proceed via a Mannich-type process. This work demonstrates how oxidative aminomethylation can be used as a useful method to introduce tertiary amines into heterocycles, thus providing an alternative method to the conventional Mannich-type reactions.151 [ReBr(CO)3(thf)]2-catalysed (thf = tetrahydrofuran) dehydrogenative borylation of primary and secondary C(sp3)–H bonds in toluene directed by a pyridyl group results in high product yield and H2 as the sole by-product even in the absence of any oxidant, 134 Organic Reaction Mechanisms 2015

external ligands, additives, or a H2 acceptor. High atom efficiency and simple reaction conditions are features of the transformation. A deuterium-labelling study revealed the reversible nature of C–H activation under the present catalytic cycle.152 A dehydrogenative olefination ofsp C( 3)–H bonds is achieved by merging the catalyst Re2(CO)10 with an alanine-derived hypervalent iodine(III) reagent (29). In the specific reaction between an alkene and 1,4-dioxane, the isolated yield of the product 2-(4-t- butylstyryl)-1,4-dioxane (30) is 66%, while the isolated yield of the reduced product, (S)-methyl 2-(2-iodobenzamido)propanoate (31), is 96%. It is concluded that cyclic and acyclic ethers, toluene derivatives, cycloalkanes, and nitriles are all alkenylated in a regio- and stereo-selective manner. It is assumed that the initial C(sp3)–H activation occurs through a radical H-abstraction pathway.153

But OAc I CO2Me O I O N H N Me Me O O O O Me (29) (30) (31)

A generalized route for organic hypervalent iodine(III) (29)-catalysed hydroxylation of aromatic and aliphatic boronic acids/esters to diversely functionalized aromatic and aliphatic alcohols is achieved in MeCN–H2O using NaIO4 as a co-oxidant in the presence of PhI. The reaction proceeds even in an inert environment. Mechanistic studies reveal that in the presence of hypervalent iodine, the arylboronic acid (an electron- demanding moiety) acts as a nucleophile for hydroxylation reactions.154 The kinetically important role of water as a co-catalyst in MeReO3-catalysed epoxidations is investigated in aqueous acetonitrile by combining kinetic measurements, DFT calculations, proton inventory experiments, and kinetic simulations. The individual epoxidation steps are weakly accelerated by water, and involve the catalytically active 2 2 peroxo complexes CH3ReO2 (𝜂𝜂 -O2)(A) and CH3ReO (𝜂𝜂 -O2)2(H2O) (B). The primary effect of water, in aqueous acetonitrile, on catalytic epoxidation arises from its acceleration of proton transfer from coordinated H2O2 to oxo ligands of MTO and A, and to 1 the hydroxo ligands of the corresponding 𝜂𝜂 -hydroperoxo intermediates. Computational results show that uncoordinated H2O molecules H-bond with peroxo ligands in A and B. Proton transfer from weakly coordinated H2O2 to the oxo ligands of MeReO3 and A is mediated by H2O molecules. Proton inventory experiments suggest that two water molecules participate directly in the rate-determining proton transfers. Kinetic simulations confirm that water acceleration of catalytic epoxidation arises primarily from 155 [H2O]-catalysed formation of the active peroxo species, altering the Re speciation. The catalytic activity of several oxo-rhenium complexes, [ReOX2(L) (PPh3)](X = Cl, Br), containing different heterocyclic ligands (32–34), is investigated in the reduction of carbonyl compounds using phenylsilane as reducing agents, in refluxing THF under air atmosphere, followed by deprotection of the resulting silyl ether with TBAF to afford the corresponding alcohol. The catalytic system PhSiH3/[ReOBr2(hmpbta)(PPh3)] proved 3 Oxidation and Reduction 135 to be the best. This system is applicable to the reduction of a large variety of aldehydes, producing the corresponding primary alcohols in good to excellent yields and good chemoselectivity.156

Me HO R N N N OH N Y N OH O Hhmpbta Y = S, O, NH R = H, OMe (32)(33) (34)

Methyltrioxorhenium(VII) (35)-catalysed highly chemo-, regio-, and stereo-selective dihydroxylation of 1,2-allenylic diphenyl phosphine oxides in the presence of dichloromethane using hydrogen peroxide as the oxidant is described. The method provides an effective pathway for the synthesis of 𝛽𝛽-carbonyl-𝛾𝛾-hydroxyl diphenyl phosphine oxides as the only product. Based on chirality transfer experiments and electrospray ionization mass spectrometry (ESI-MS) studies of 18O-labelled products, the major reaction pathway is proposed to proceed via regioselective epoxidation of the electron-rich carbon–carbon double bond and a subsequent intermolecular nucleophilic attack of a water molecule on the in situ formed epoxide via neighboring group participation (NGP), followed by a rearrangement.157

O H2O O O Re O O Me

(35)

Platinum and Iridium The hydrogenation of 3,4-dichloronitrobenzene (3,4-DCNB) and 3,4-dichloro-N- phenylhydroxylamine (3,4-DCPHA), carried out under static conditions over a platinum catalyst on a porous support, is studied in the presence of pyridine. The effect of the inhibitor (small admixtures of pyridine) on the dehalogenation of 3,4- dichloroaniline (3,4-DCA) shows that pyridine significantly decreases the rate of dehalogenation because pyridine competes with both chloroaniline and hydrogen. The kinetic data on the consumptions of 3,4-DCA, 3,4-DCPHA, and 3,4-DCNB are evidence that their hydrogenation in the presence of pyridine is satisfactorily describable in terms of the concept of reaction inhibition, which confirms the applicability of the approaches used in enzyme catalysis.158 2− 3 A PtCl4 -catalysed terminal-selective C(sp )–H oxidation of protonated aliphatic amines using CuCl2 as the oxidant in presence of H2SO4 with the highest TONs and selectivity is described. Protonation of the amine is critical because it renders the 136 Organic Reaction Mechanisms 2015 substrates water-soluble, and prevents deactivation of the catalyst/oxidant by amine binding. And the inductive electron-withdrawing ammonium cation electronically deactivates the proximal C–H bonds, resulting in high selectivity for terminal C(sp3)–H sites that are remote to nitrogen. The method is effective for the terminal-selective C(sp3)–H oxidation of a variety of primary, secondary, and tertiary amines.159 DFT calculations for Pt-catalysed reduction of amides with 1,2-bis(dimethylsilyl)-benzene (BDSB) suggest that the platinum-catalysed hydrosilylation of the C=O bond proceeds IV via a H2Pt Si2 intermediate and that the catalytic cycle is initiated by the insertion of the amide C=O bond into the Pt–H bond (Chalk–Harrod mechanism). This inser- IV tion occurs readily because a Pt–H bond of H2Pt Si2 is highly activated by strong 𝜎𝜎-donation from the silyl groups. Further studies have revealed the mechanisms of reductive deoxygenation, which proceed via a Pt(II) hydride-silyl intermediate having a characteristic bicyclic structure.160 2− + The PtCl6 oxidation of l-asparagine (Asn) to 𝛼𝛼-formyl acetamide, NH4 ion, and + 2+ 3+ 4+ CO2, catalysed by Ag , Pd , Cr , and Zr (transition metals), in H2SO4 is first order 2− in PtCl6 but orders with respect to Asn, H2SO4, and transition metals are less than unity. The rate decreased with increasing ionic strength and dielectric constant. The cat- 3 2 4 alytic order is Ag+ > Cr + > Pd + > Zr +. Electron transfer is facilitated by the adducts between the transition metal and the carboxylate oxygen on Asn. The uncatalysed oxidation by Pt(IV) takes place by an inner-sphere mechanism in which, following substrate binding, the Pt(IV) is reduced to Pt(II) in a one-step two-electron transfer process.161 Hydrogenation of CO2 catalysed by Ir complexes bearing N,N-bidentate ligands is reported. The catalytic performance is enhanced by a ligand containing hydroxy groups as proton-responsive substituents, by an electronic effect of the oxyanions and a pendent-base effect through secondary coordination sphere interactions. In particular, [(Cp*IrCl)2(TH2BPM)]Cl2 (TH2BPM = 4,4,6,6-tetrahydroxy-2,2-bipyrimidine) promotes the catalytic hydrogenation of CO2 in basic water. Newly designed complexes with azole-type ligands have also been applied to CO2 hydrogenation and found to have much higher catalytic efficiencies than the unsubstituted bipyridine complex [Cp*Ir(bpy)(OH2)]SO4. Furthermore, the introduction of one or more hydroxy groups into ligands such as 2-pyrazolyl-6-hydroxypyridine, 2-pyrazolyl-4,6- dihydroxypyrimidine, and 4-pyrazolyl-2,6-dihydroxypyrimidine enhance the catalytic activity. Hence, the incorporation of additional electron-donating functionalities into proton-responsive azoletype ligands is effective for promoting further enhanced 162 hydrogenation of CO2. DFT calculations are performed to elucidate the mechanism of the dehydrogenative oxidation of various primary alcohols (or 𝛼𝛼-hydroxy carboxylic acids) and the dehydrogenative coupling of alcohols with ammonia catalysed by the same water-soluble Cp*Ir complex bearing a 2-pyridonate-based ligand (A-Ir). Another two new catalysts A-Rh and A-Os are computationally designed for the dehydrogenative oxidation of alcohols. The plausible pathway for alcohol dehydrogenation includes three steps: (i) alcohol oxidation to aldehyde; (ii) the generation of dihydrogen in the metal coordination sphere; (iii) the liberation of dihydrogen accompanied by the regeneration of active catalyst A. Among these, step (i) follows a bifunctional concerted double hydrogen transfer mechanism rather than 𝛽𝛽-H elimination, and for step (ii) the energy barriers involving the 3 Oxidation and Reduction 137 addition of one or two water molecules are higher than that in the absence of water. These results also confirm that A-Ir can be applied in the dehydrogenation of various 𝛼𝛼- hydroxy carboxylic acids by a similar mechanism. A-Ir is also efficient for the coupling reactions of various primary benzyl alcohols with ammonia to afford amides.163 The mechanism of imine reduction by formic acid, catalysed by Ir-catalysts (36) and (37) that have only one coordination site (iridicycle catalyst), is investigated by DFT, NMR spectroscopy, and kinetic measurements. The NMR and kinetic studies suggest that the transfer hydrogenation is turnover-limited by the hydride formation step. DFT calculations reveal that hydride formation between (36)or(37) and formate probably proceeds by an ion-pair mechanism, whereas the hydride transfer to the imino bond occurs in an outer-sphere manner. In the gas phase, in the most favourable pathway, the activation energies for hydride formation and transfer steps are calculated. Introducing one explicit methanol molecule into the modelling alters the energy barrier significantly. DFT investigation further shows that methanol participates in the TS of the turnover- limiting hydride formation step by hydrogen-bonding to the formate anion and thereby stabilizing the ion pair.164

Me Me Me Me Me Me

MeO Me Me Me Me H N Ir Cl N Ir Cl

Me H

CN (36) (37)

+ The molecular structure of the prepared unbridged biscarbene [Ir(cod)(MeIm∩Z)2] complexes (∩Z = pyridine-2-ylmethyl) having functionalized N-heterocyclic ligands featuring 2-methoxybenzyl, pyridin-2-ylmethyl, and quinolin-8-ylmethyl show an antiparallel disposition of the carbine ligand, which minimizes the steric repulsions between the bulky substitutents. The complexes, however, are dynamic in solution, resulting in two inter-converting diastereomers having different dispositions of the + functionalized NHC ligands. The complex [IrH2(MeIm∩Z)2] is prepared by the reaction of the corresponding Ir(I) complex with H2. The complexes are efficient catalyst precursors for transfer hydrogenation of cyclohexanone in 2-propanol/KOH, exhibiting comparable activity, which is independent of both the wingtip type at the NHC ligands and the counterion. Mechanistic studies support the involvement of diene free bis NHC Ir(I) intermediates in these catalytic systems. DFT calculations show that a Meerwein–Pondorff–Verley (MPV) mechanism involving the direct hydrogen transfer at the coordination sphere of the Ir centre might compete with the well-established hydrido mechanism. Indirect evidence of a MPV-like mechanism is found for the catalyst precursor having NHC ligands with a pyridine-2-ylmethyl wingtip.165 138 Organic Reaction Mechanisms 2015

The combination of [Ir(cod)Cl]2 and 1,10-phenanthroline is a highly effective catalyst system for the selective transfer hydrogenation of nitroarenes to anilines in the presence of 2-propanol which acts as a hydrogen donor. The protocol has wide substrate scope. The mechanistic investigation, through real-time detection and a series of controlled experiments with possible intermediates, indicates that the transformation proceeds via both phenylhydroxylamine and azobenzene intermediates and the reduction of hydra- zobenzene leading to aniline might be the rate-determining step.166 The Ir complex (38) catalyses the transfer hydrogenation of various nitrogen heterocycles, including but not limited to quinolines, isoquinolines, indoles, and pyridinium salts, in an aqueous solution of HCO2H/HCO2Na (hydride source) under mild conditions. The catalyst shows excellent functional-group compatibility and high TON (up to 7500). Mechanistic investigation of the quinoline reduction suggests that the transfer hydrogenation proceeds via both 1,2- and 1,4-addition pathways, with the catalytic turnover being limited by the hydride transfer step.167

Me Me Me Me Me Cl Me Ir N OMe

(38)

The use of chiral dinuclear [{Ir(H)(diphosphine)}2(𝜇𝜇-Cl)3]Cl complex as catalyst in the asymmetric hydrogenation of isoquinoliniums to the corresponding chiral 1,2,3,4- tetrahydro isoquinolines in high yields with excellent enantioselectivities indicates that the isoquinolinium chlorides generated inhibit the formation of catalytically inactive dinuclear trihydride complexes, which are otherwise readily generated in the hydrogenation of salt-free isoquinolines. The function of the chloride anion of the isoquinolinium chloride is elucidated, and a new outer-sphere mechanism involving the coordination of the chloride anion of the substrates to an iridium dihydride species along with a hydrogen bond between the chloride ligand and the N–H proton of the 168 isoquinolinium chloride is proposed. ee The Ir complex (39) is a highly efficient catalyst for the asymmetric hydrogenation of methyl 𝛽𝛽-alkyl-𝛽𝛽-ketoesters under H2 in the solvent MeOH and base t-BuOK for the synthesis of chiral 𝛽𝛽-alkyl-𝛽𝛽-hydroxyesters in high yields (91–98%) and excellent enantioselectivities (95–99.9 % ee). The TONs are up to 35.5 × 104 regardless of the electronic and steric properties of the alkyl group. Full conversion and an enantioselec- 169 tivity of 95% ee are reported at a catalyst loading of 0.001 mol% (S/C = 100,000). ee DFT calculations are used to investigate the mechanism of the trimerization of alkynes in the presence of TpIr (Tp = hydrotris(pyrazolyl)borate. The calculations suggest that 3 Oxidation and Reduction 139

Me Ar Me P Cl Me H Ar Ir Ar = N H S H Me S Me Me (39) the initial oxidative coupling of two alkyne molecules yields an iridacyclopentadiene intermediate, which reacts with a third alkyne molecule to give a benzene TpIr complex. There are two possible mechanisms for the formation of the benzene complex, namely the intramolecular 4 + 2-cycloaddition and Schore mechanism. The formation of unsubstituted benzene from acetylene molecules was initially investigated, followed by the oxidative coupling reaction of 1,4-dimethyl-2-butyne- 1,4-dioate (CH3OCOC≡CCOOCH3), and then the formation of the polymethyl benzene from 2-butyne (H3CC≡CCH3). In the reaction of unsubstituted acetylene, the 4 + 2-cycloaddition is more favourable than the Schore mechanism, whereas the reaction could proceed only via the Schore mechanism in the reactions of substituted alkynes. Notably, the effects of additional water molecules on the stability of the reaction intermediates were also evaluated because the water complexes of several intermediates have been experimentally isolated and identified.170 The Ir complexes (40) and (41) have been used as catalysts for the asymmetric hydrogenation of furans and benzofurans to the corresponding tetrahydrofurans and dihydrobenzofurans. Catalyst (40) gives high yields and good to excellent enantioselectivities for a range of monosubstituted alkyl- and aryl-furans and 2-alkylbenzofurans in trifluorethanol. The complex (41) is the catalyst of choice for the hydrogenation of 3,6-dimethylbenzofuran and 5-bromo-3,6-dimethylbenzofuran in dichloromethane. Asymmetric hydrogenation of a 3-methylbenzofuran derivative is a key step in the formal total synthesis of 171 (−)-thespesone. ee + +

Me BArF− Me BArF− Me O Me O P Me P Me N Me N Me Ir Ir Me Me Me Me Me

(40) (41)

Asymmetric hydrogenation of quinazolinium HCl salts in dichloromethane under H2 using Cl-bridged dinuclear iridium complex (42) as the catalyst affords the tetrahy- droquinazoline and 3,4-dihydroquinazoline in high yield (75%) with enantioselectivity 140 Organic Reaction Mechanisms 2015

(92%), along with dihydroquinazolines in 22% yield. The counter-anions of the substrate salt affect product distribution. Optically pure 3,4-dihydroquinazolines were used as 172 potential precursors of chiral NHC ligands. ee

O O P P O Cl O H Ir Ir H Cl O O P Cl P O O

(42)

The bench-stable Ir catalyst (43) catalysed the asymmetric transfer hydrogenation of ketones in the presence of the base t-BuOK to the corresponding chiral alcohols with high enantioselectivities. The yield and enantioselectivity of the alcohols at 0.1 mol% loading of the catalyst are 95% and 91% ee, respectively. However, diminished yield (45%) and increased enantioselectivity (97%) were observed at 0.01 mol% of the catalyst loading. Under the last set of conditions (S/C = 10,000), the TON of (43) was estimated to be 4500.173 ee CF3

Cl Ir

N N

F3C

(43)

Group VIII Metals: Iron, Palladium, Rhodium, Ruthenium, and Osmium For the transfer hydrogenation of the polar bonds of ketones, enones, and imines, efficient catalysts are bis(isonitrile) Fe(II) complexes (44), which bear a C2-symmetric diamino (NH)2P2 macrocyclic ligand. The yield is up to 99.5%, and enantioselectivity is up to 99% ee with low catalyst loading. The catalyst is easily tuned by modifying 174 the substituents of the isonitrile ligand. ee 3 Oxidation and Reduction 141

H (BF4)2

PH Ph N H Fe C C N N R R P Ph

(44)

Significant enhancement of both the rate and chemoselectivity is achieved in FeCl3-catalysed oxidative coupling of phenols in ClCH2–CH2Cl with t-BuOOt-Bu as the terminal oxidant. High acceleration is observed in 2,2,2-trifluoroethanol or 2,2,2-trichloroethanol, affording BINOL with 75% and 97% conversion, respectively. Almost complete consumption of 2-naphthol is observed when the reaction is performed in 1,1,1,3,3,3-hexafluoropropan-2-ol. The generality of this effect is examined for cross-coupling of phenols with arenes and polycyclic aromatic hydrocarbons and of phenol with 𝛽𝛽-dicarbonyl compounds. The new conditions are utilized in the synthesis of 2′′′-dehydroxycalodenin-B in four synthetic steps.175 The alkaline hexacyanoferrate(III) oxidation of procainamide to 4-aminobenzoic acid 3− and (E)-ethene-1,2-diamine is first order in Fe(CN)6 and less than unit order in procainamide and OH− concentrations. The oxidation of 1 mol of procainamide requires 3− 2 mol of Fe(CN)6 . Increasing the ionic strength and decreasing the dielectric constant of the medium increases the rate of reaction. A suitable mechanism is proposed, and the rate law is derived and verified. The activation parameters for the slow step ofthe mechanism and thermodynamic quantities are calculated.176 3− The kinetics of oxidation of ethyl vanillin by Fe(CN)6 in aqueous alkaline solution is fractional order in substrate and OH− ion and first order in the oxidant. The 4− rate-determining step is the outer-sphere formation of Fe(CN)6 and free radicals, fol- 3− lowed by the rapid oxidation of free radicals by Fe(CN)6 to give the products. Added 4− 177 Fe(CN)6 has a retarding effect on the reaction rate. 3− The kinetics and mechanism of oxidation of sulfanilic acid by Fe(CN)6 catalysed by Os(VIII) and Ru(III) have been studied. The uncatalysed reaction, which occurs simultaneously, is suspected to benefit from catalysis by any trace metal ion impurity present. 4− 178 The rate of the reaction is retarded by Fe(CN)6 . 3− The kinetics of oxidation of salicylaldehyde by Fe(CN)6 in aqueous alkaline medium 3− − is first order in Fe(CN)6 , fractional order in OH ion, and inverse fractional order 4− in substrate; Fe(CN)6 has a retarding effect, but the rate increases with increasing ionic strength and dielectric constant of the medium.179 Oxidation of tertiary noncyclic aliphatic amines to amides by PhCO3t-Bu under mild conditions and optimized water content (11 equiv) is catalysed by FeCl3 in the presence of picolinic acid as additive and occurs in 58% yield under a nitrogen atmosphere. Mechanistic studies suggest that 142 Organic Reaction Mechanisms 2015 hemiaminals are likely intermediates, and the catalytic system can be employed for other C𝛼𝛼–H oxidations of amines. Thus, the protocol is expected to expedite the synthesis of oxidative metabolites relevant for toxicity studies of pharmaceutically active compounds under mild conditions.180 The oxidation of hydrocarbons (cumene, ethylbenzene, [D10]ethylbenzene, cyclooc- tane, cyclohexane, and 9,10-dihydroanthracene) is studied with the FeVO–TAML complex (45) (TAML = tetra-amidato macrocyclic ligand). Values of log k2 (where k2 is the statistically normalized second-order rate constant) correlate linearly with ‡ DC–H, the C–H bond dissociation energies, but ΔH does not. The point for 9,10- ‡ dihydroanthracene for the ΔH versus DC–H correlation lies markedly off a common straight line of best fit for all other hydrocarbons, suggesting that it proceeds via an alternate mechanism than the rate-limiting C–H bond homolysis promoted by (45). Contribution from an electron-transfer pathway may be substantial for 9,10- dihydroanthracene. There is a KIE of 26 with ethylbenzene and [D10]ethylbenzene, indicating tunneling.. The diiron(IV) 𝜇𝜇-oxo dimer, which is often a common component of the reaction medium involving (45), also oxidizes 9,10-dihydroanthracene, although its reactivity is three orders of magnitude lower than that of (45).181

O Me O Me O N N FeV Me N Me N Me

O Me O

(45)

FeCl2-catalysed trifluoromethylation of enamides can be achieved with 84% yield and complete 𝛽𝛽-regioselectivity using 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (Togni’s reagent) as the electrophilic CF3 source in CH2Cl2. The transformation is totally regioselective at the C(3) position of enamides and exhibits broad substrate scope and good functional group tolerance. The nature of the electron-withdrawing aromatic group on the nitrogen atom leads to the desired trifluoromethylated enamides with high yields.182 The mechanism of O-atom transfer to a wide variety of alkenes using the [FeV(O)− (biuret-TAML)]− complex (46) is studied at room temperature. The formation of both cis- and trans-stilbene epoxides (73:27) on using cis-stilbene suggests the formation of a radical intermediate, which allows C–C bond rotation. Detailed DFT calculations also indicate that the epoxidation proceeds via the generation of a radical intermediate through an electrophilic attack on the alkene followed by a very fast (low-barrier) ring- closing step. The epoxide is formed with modest yields and TONs when (46) is used as the catalyst with NaOCl as oxidant.183 The mechanism for asymmetric hydrogenation of 2H-1,4-benzoxazines with Knölker’s iron complex in the presence of chiral phosphoric acids (47) is 3 Oxidation and Reduction 143

O O Me Me O N N FeV N Me N Me N O

O Me

(46) computationally investigated at the DFT-D level of theory with models of up to 160 atoms. The adduct between the iron complex and the deprotonated acid is the resting state of the system. A step-wise hydrogenation mechanism, in which the phosphoric acid acts as the proton donor, follows the rate-limiting H2 splitting. C–H⋅⋅⋅O interactions between the phosphoric acid and the substrate are involved in the stereocontrol at the final hydride transfer step. The computed enantioselectivities with two different chiral phosphoric acids show excellent agreement with experimental 184 values, allowing the identification of the interactions involved in the stereocontrol. ee Brønsted acid Me Me Me Si

HO Knölker's complex O O Me P Si Fe CO O Me H Me CO O H H H N

O Benzoxazine (47)

The Fe(OTf)3-catalysed oxidation of pyrrolones with O2 in CH3CN results in the formation of reactive N-acyliminium ion intermediates that undergo nucleophilic additions with primary and allylic alcohols to give the corresponding products in moderate to good yields.185 Direct 𝛼𝛼-arylation of cyclic and acyclic ethers with azoles is achieved by CDC using a novel combination of FeF2 and t-butyl peroxybenzoate as the catalyst and TBHP as the oxidant, in THF with 1,2-dichloroethane as co-solvent. FeF3 is found to be as efficient as FeF2.This oxidative method allows the efficient C(2)-alkylation of a variety of (benzo)azoles, constituting straightforward access to heterocycles of utmost medicinal significance and highlighting the convenient use of feedstock substrates and iron catalysts. A preliminary mechanism supported by DFT calculations is discussed.186 144 Organic Reaction Mechanisms 2015

OH O OH or O or electron transfer Me Me Me 18O Me 18OH N N OMe + Fe4 N N OMe Me N N radical rebound N N N Me N

Me Me 18 OH Me Me OMe (48) OMe L dissociative pathway

Scheme 3 3 Oxidation and Reduction 145

During the synthesis of [(N4Py)OMe,Me(L)FeIV(O)] (48)(OTf)+, non-heme ironIV-oxospecies at room temperature, other species such as iron(III)-hydroxide, iron(III)-alkoxide, and hydroxylated-substrate-bound iron(II) are detectable intermediates. Compound (48) forms Fe(III) intermediates during hydrogen-atom abstraction (HAA) from the C–H bond. The study reveals that there are three C–H oxidation pathways depending on the stability of the radical generated after HAA: (i) the electron transfer pathway (radicals are more stable), (ii) radical rebound pathway (radicals are moderately stable), and (iii) dissociative pathway (radicals are least stable). The specific substrates undergoing these pathways are shown in Scheme 3.187 II The mechanism of the non-heme [Fe (CH3CN)(N4Py)(ClO4)]ClO4, (N4Py = N,N-bis (2-pyridylmethyl)-N-bis(2-pyridyl)methyl-amine) complex catalyses Baeyer–Villiger (B–V) oxidation of cyclohexanones by O2 to 𝜀𝜀-caprolactones with co-oxidation of various aldehydes. The kinetics of formation and the reactivity of the trapped and spectroscopically characterized oxoiron(IV) intermediate are also reported.188 The FeCl3-catalysed oxidative dehydrogenative coupling of a wide variety of tetra- zoles and ethers, in ethyl acetate with TBHP as the oxidant, results in formation of the corresponding hemiaminal derivatives in moderate to good yields.189 A direct oxidative cross-coupling between terminal alkynes and CuCN in methanol, in the presence of FeCl3 as the sole additive under air atmosphere, is reported to form 1-cyanoalkynes with moderate to good yields.190 BINOL-derived chiral (cyclopentadienone)iron complexes are synthesized and converted in situ to the corresponding (hydroxycyclopentadienyl) complexes by employing K2CO3 as activator. The (hydroxycyclopentadienyl) complexes catalyse the asymmetric hydrogenation of ketones to the corresponding alcohols and show moderate to good enantioselectivity. Very low conversions (<5%) are observed in the absence of H2, suggesting that the hydrogenation pathway dominates over the transfer hydrogenation from i-PrOH. The complex bearing methoxy substituents at the 3,3′-positions of the binaphthyl moiety (49) proved remarkably more enantioselective than the unsubstituted ones (50) and reached the highest level of enantioselectivity (up to 77 % ee) with chiral (cyclopentadienone)iron 191 complexes. ee Me Me OMe Me Me Si Si Me Me O O Me Me OMe Si Si Fe Me Fe OC OC Me Me CO Me CO OC OC (49) (50)

Eleven chiral cyclopentadienone–iron complexes, based on the parent complex (51), have been synthesized for use as pre-catalysts in the asymmetric hydrogenation of ketones. These complexes differ from each other in the substituents at the 3,3′-positions 146 Organic Reaction Mechanisms 2015

of the binaphthyl residue (H, OH, OR, OCOR, OSO2R) or at the 2,5-positions of the cyclopentadienone ring (trimethylsilyl or Ph). They are highly stable and tolerate the conditions required for the reactions of several functional group interconversions. Complex (51) (cyclopentadienone/hydroxycyclopentdienyl) remains the preferred pre-catalyst for the asymmetric hydrogenation of aldehydes and ketones, providing the best conversion and ee (up to 77%) to date. Substitution at the 3,3-positions of the binaphthyl system affects both the activity and the enantioselectivity in an unclear manner. The 2,5-bis(phenyl)-substituted compound prepared from (51) exhibits low catalytic activity and reversal of the stereochemical preference in the asymmetric hydrogenation of ketone. This finding suggests that both the binaphthyl 3,3-substituents and the cyclopentadienone 2,5-substituents of the new catalysts play a role in the transmission of the stereochemical information.192 ee OMe

OMe OC Fe OC CO

(51)

The reduction of ketones and aldehydes to the corresponding secondary and primary alcohols, catalysed by the amine–bis(phenolate) iron(III) complex (52) (D = CH2Furf where Furf = tetrahydro-2-furfuranyl), is achieved in 95% yields in CD3CN, triethoxysi- lane, and aqueous NaOH. The catalyst is easily accessible, stable towards moisture and air, and has a broad substrate scope, giving good to excellent yields. The system chemoselectively reduces ketones over esters, imines, olefins, and even conjugated olefins, offering impressive chemoselectivity towards the carbonyl functionality. Preliminary experiments showed that the optimized catalyst also had the potential to 193 hydrosilylate CO2. Me Me N

O O Fe D Me Cl

(52) The yield of the asymmetric hydrogenation product of benzoxazinone in toluene in the presence of Fe3(CO)12, phenanthridine, and chiral Brønsted acid (53,R= 2,4,6- (i-Pr)3–Ph) under H2 atmosphere is affected by the presence or absence of the tris(4- methoxyphenyl)phosphane (TMP) ligand. The yield of dihydrobenzoxazinones in the 3 Oxidation and Reduction 147 absence of TMP is 99% with moderate enantioselectivity (76:24 er), whereas the yield in the presence of TMP is 92% with enantioselectivity at 84:16 er. It is noteworthy that 3-alkyl-substituted benzoxazinones undergo highly enantioselective reduction. The key to the success is the utilization of a non-chiral ligand to reduce disadvantageous 194 background reactions by tuning the catalytic activity of Fe3(CO)12. ee R

O O P OH O

(53)

Detailed kinetic studies are made to investigate the mechanism of Pd(OAc)2-catalysed aziridination of tetramethylmorpholinone. The added AcOH suppresses the formation of the off-cycle bis-amine intermediate complex and significantly increases the overall rate of reaction. DFT calculations have given an insight into the regioselectivity of cyclopalladation and have provided a plausible explanation for the resulting aziridine product.195 The use of trialkylammonium salts in a glycol solvent (hydrogen-bond donor) in presence of the catalyst bis(dibenzylideneacetone)palladium(0), (Pd(dba)2), (54) and the ligand spiro-di(1,1′-indanyl) bisphosphine enables asymmetric reductive Heck reaction of aryl halides to afford 3-arylindanones with high ee, and help halide dissociation from neutral arylpalladium complexes to access cationic stereoselective pathways under mild reaction conditions.196 ee O

Pd O

(54)

A series of functionalized allenes in acetone undergo Pd(OAc)2-catalysed olefin- directed regio- and stereo-selective arylation of allenes by PhB(OH)2 in presence of 1,4-benzoquinone and LiOAc to give 1,3,6-trienes in good to excellent (∼90%) yields. The olefin unit is crucial for realizing the transformation. Mechanistic studies have 148 Organic Reaction Mechanisms 2015 confirmed that the allene attack on Pd(II) requires an additional coordination ofanolefin or acetylene and that cleavage of the allenylic C–H bond is the rate-determining step.197 Pd(OAc)2-catalysed ortho-arylation of N,N-dimethylbenzylamine derivatives with aryl boronic acids via selective aryl C–H activation to construct biaryl skeletons in DMF using 1,4-benzoquinone as oxidant in presence of HOAc under air and mild conditions is described. These transformations are an efficient method for constructing C–C bonds in organic synthesis. Various substrates proved to be efficient coupling partners, furnishing the corresponding ortho-mono- or di-arylated arenes in moderate to good yields under mild conditions.198 An open Pd(OAc)2-catalysed oxidative reaction of dihydropyrans in the presence of ′ ′ N,N,N ,N -tetramethyl cyclohexyldiamine ligand, an alcohol, CuCl2, and air leads to the formation of the corresponding ortholactone in good to excellent yields with a very high level of chemoselectivity and functional group tolerance. The reduced Pd(0) is regenerated to Pd(II) by CuCl2 and air. Mechanistic studies confirm that the reaction proceeds by a Wacker-type mechanism.199 Dehydrogenative coupling of secondary phosphine oxides with a variety of terminal alkynes in THF is efficiently catalysed by Pd(OAc)2 in the presence of AgBF4 as the additive to produce the corresponding alkynylphosphine 200 oxides in 95% yields. A reaction mechanism is proposed. A series of chiral 𝛼𝛼-amino acid derivatives have been synthesized with excellent ee by Pd(OAc)2-catalysed enantioselective oxidative C–H arylation of N-aryl glycine esters with aryl boric acids using + − 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetra-fluoroborate (T BF4 ) as the oxidant in presence of DCE (solvent) and (4S,4′S)-4,4′-diiso propyl-2,2′-bis(2-oxazoline) 201 as a ligand at 60 ∘C under an argon atmosphere. The kinetics of oxidation of substi- ee tuted 5-oxoacids, RC6H4CO(CH2)3CO2H (R = H, p-Me, p-OMe, p-C6H5, p-Cl, p-Br, and m-NO2), by perborate ion to benzoic, succinic, and boric acid in aqueous AcOH are first order in both perborate ion and 5-oxoacid and second+ orderinH ions. Lowering the dielectric constant of the reaction medium enhances the rate. The reactivity order among the 5-oxoacids is p-methoxy ≫ p-Me > p-Ph > –H> p-chloro > p-bromo > m-nitro. The + 202 oxidation is faster than for H2O2 and features the H2BO3 ion as the reactive species. The Pd(OAc)2-catalysed oxidative Heck coupling of 2,2-disubstituted cyclopentene- 1,3-dione and arylboroxine is achieved in DMF in the presence of 1,10-phenanthroline using molecular oxygen as the oxidant. The direct coupling onto the 2,2-disubstituted cyclopentene-1,3-dione core provides a novel and expedient way of enantioselec- 203 tively desymmetrizing all-carbon quaternary centres. The Pd(OAc)2-catalysed dehydrogenative Heck reaction of furans and thiophenes with cinnamic acid and stilbene derivatives has been conducted in AcOH medium with benzoquinone as oxidant in the presence of the ligand 4,5-diazafluorenone to provide trisubstituted unsaturated compounds in 70% yields with high stereoselectivity at room temperature. The conversion is 100% with yield 90% if O2 is used as the oxidant in place of benzoquinone. According to the results of kinetic and competitive experiments (which suggested an electrophilic pathway) and ESI-MS studies (which led to the characterization of the catalytic intermediates involved in arene activation and alkene insertion), the ligand has an influence on all steps of the catalytic cycle, thatis, C–H bond activation, alkene insertion, stereodetermining step, and regeneration of 204 the catalyst. Pd(OAc)2-catalysed geminal bis(silane)-controlled oxidative Heck 3 Oxidation and Reduction 149 reaction of enol ethers with terminal alkenes, in AcOH with hexane as the cosolvent and benzoquinone as the oxidant, proceeds with an 𝛼𝛼,𝛽𝛽-coupling regioselectivity to form the desired 1,3-dienes in 90% yields with high Z,E-selectivity. The resulting 1,3-dienes are valuable synthons in Sakurai homoallylation with acetals to generate 𝛼𝛼-substituted-𝛾𝛾-keto esters with good anti-selectivity. The silyl group also displayed a significant impact on the coupling efficiency. The reaction of 3,3-bis(trimethylsilyl) enol ether or 3,3-bis(dimethylphenylsilyl) enol ether with ethyl acrylate only led to a 205 complex mixture. de One-step synthesis of biologically relevant dibenzodiazepines (DBDA) by the reaction of o-bromoaldimine with o-bromoaniline, using Pd(OAc)2 as the catalyst in the presence of the ligand SPhos with Cs2CO3 as the base in THF, is described. Several DBDAs containing EWGs (CN, F, NO2) and electron-donating groups (OMe) were prepared. DFT calculations indicate that the regioselectivity at the oxidative addition step is due to the more stable nature of the adduct formed by aldimine and the Pd(0) catalyst than the adduct formed with the amine. The barrier for the oxidative addition at the C–Br bond of the aldimine is lower than at the C–Br bond of the aryl amine. The unusual formation of a seven-membered ring over the six-membered ring at the final step of the catalytic cycle has been rationalized.206 The presence of CuCl2 is essential for the dioxygenation of a series of alkenes with O2, with yields up to 94% when using [PdCl2(PhCN)2] as the catalyst and AgNO2 as co-catalyst, to achieve efficient catalytic turnover in the presence of the solvent system AcOH/Ac2O/MeNO2. NO2, formed from nitrite, is a potential intermediate in the catalytic cycle. The low yield in the dioxygenated products on replacing AgNO2 with NaNO2 indicates that the Ag + counter-ion is critical for efficient oxidation. Similarly, increasing the amount of the nitromethane co-solvent improved the kinetics and repro- ducibility of the reaction. Acidification of the catalytic system enabled catalytic amounts of NOx to oxidize an alkyl–Pd(II) intermediate and facilitate C–O bond-forming reductive elimination to provide difunctionalized products. Experiments using 18O-labeling demonstrated that both oxygen atoms in the difunctionalized products are derived from one molecule of acetic acid.207 The intramolecular C–H/C–H coupling of 3-aryloxythiophenes and 3-aryloxybenzo [b] thiophenes in propionic acid is effectively catalysed by Pd(TFA)2 in the presence of AgOAc as oxidant to give the corresponding cyclized products thieno[3,2-b]benzofurans and [1]benzothieno[3,2-b]benzofurans.208 Branched-selective oxidative Heck coupling reactions between arylboronic acids and electronically unbiased terminal alkenes, under O2 (1 atmospheric pressure) and without any additives, using the Pd(TFA)2/dmphen system as catalyst, result in the synthesis of highly regioselective 𝛼𝛼-substituted vinylarenes with 71% yield (72% yield if arylboronic acid is the limiting reagent with excess alkene). A broad array of functional groups, including aryl halide, allyl silane, and carboxylic acids are tolerated. 𝛼𝛼-Alkyl vinylarenes are important precursors to chiral building blocks (via asymmetric hydrogenation and other transformations) and intermediates in the synthesis of bioactive natural products.(dmphen = 2,9-dimethyl-1,10-phenanthroline, NMP = N-methylpyrrolidone).209 C–H bond acylation of acetanilides with benzylic alcohols to give the corresponding ketones is achieved in yields up to 98% under aqueous conditions using Pd(OAc)2 as 150 Organic Reaction Mechanisms 2015 the catalyst, TBHP as oxidant, and a catalytic amount of TFA as additive. Mechanism studies show that a bimetallic palladium cyclopalladated complex might be involved in the catalysis.210 The Pd[P(o-tolyl)3]2-dppe-catalysed (dppe = diphenylphosphinoethane) umpolung cyclization of allylic acetate–aldehyde using HCO2H/Bu3N as a terminal reductant in presence of acetonitrile (solvent) affords the cyclic product in 78% yield. The cyclization is not promoted by Pd[P(o-tolyl)3]2. The use of chiral (S)-SEGPHOS (55) (Ar = phenyl or 3,8-xylyl) in place of dppe increased the yield to 86% and up to 97% ee. The formate does not cause allylpalladium reduction under the catalysis. The highly 1 stereoselective cyclization would proceed through a cationic 𝜂𝜂 -allylpalladium ligated 211 by diphosphine. ee

P O

O P

(55)

The synthesis of 3-bicyclo[4.1.0]heptan-5-ones in water is achieved from Pd(OAc)2- catalysed oxidative 6-exo-trig cyclization of 1,6-enynes using t-BuONO as an oxidant. The reaction is favoured by O2. The cyclization of 1,6-enyne proceeds through a hydration, 6-exo-trig cyclization, and cyclopropanation cascade, and provides a mild and selective access to diverse bicyclo[4.1.0]heptan-5-one skeletons, including 3-azabicyclo[4.1.0]heptan-5-ones, 3-oxabicyclo[4.1.0]heptan-5-ones, and 1H cyclopropa[b]naphthalen-2(1aH)-ones, in moderate to good yields with excellent functional group tolerance and stereoselectivity.212 The cross-esterification between two different alcohols, various benzylic alcohols, and aliphatic alcohols, is catalysed by PdCl2(PPh3)2 in the presence of benzyl chloride as the oxidant. The cross-esterification takes place with excellent yields, but the need tousean excess amount of aliphatic alcohols with the oxidant benzyl chloride is consistent with the proposed mechanism.213 The bis(N-heterocyclic carbene) Pd(II) peroxocarbonate complex (56) is converted to the corresponding PdCO3 on undergoing an oxygen-atom-transfer (OAT) reaction towards a phosphine and a sulfoxide. It is proposed, on the basis of the remarkable acceleration of the rate of a sluggish OAT reaction towards triphenyl phosphine on the addition of LiCl, that the chloride ion induces the liberation of the peroxocarbonate moiety from the coordination sphere of palladium.214 The intramolecular Mizoroki–Heck (MH) reaction takes place between 1-iodo-2-(2- methyl prop-2-enyloxy)benzenes (57) and the catalyst Pd(COD)Cl2 in presence of (n- Bu)4NBr, base K3PO4 and N,N-dimethylacetamide under nitrogen to give the alkyl- Pd(II) intermediate (58) and 2,3-dihydrobenzofuran (59) in the synthesis of dimeric 3 Oxidation and Reduction 151

O Me Me Me Me O O Me ITmt PdO Me N N ITmt ITmt Me Me (56) dihydrobenzofuran (60). The intermediate (58), being sufficiently stable and ideally positioned, activates the C(sp3)–H bond of (59) by the auxiliary coordination of the oxygen atom on the furan ring, thus leading to a dimeric dihydrobenzofuran product (60) by the sequential CDC reaction.215

Me PdX H Me X Pd(COD)Cl2 + CH 2 Mizoroki–Heck O O O reaction (57) Me (58) (59) Pd-functionalization of unactivated C(sp3)–H bonds O Me

Me O (60)

The synthesis of 𝜋𝜋-conjugated polyaromatic heterocycles from the dehydrogenative annulation of imidazo[1,2-a]pyridine with diarylalkynes is achieved in 78% yield using ∘ Pd(OAc)2 as the catalyst and Cu(OAc)2⋅H2O as the oxidant in DMSO at 110 C. An array of 2,3,4-triarylphenyl-1,7b-diaza-cyclopenta[cd]indene derivatives with broad functionalities are obtained in high yields through dual activation of C–H bonds without any assistance of hetero-atom-containing directing groups.216 A novel and facile Pd(OAc)2-catalysed direct phosphonation of imidazo[2,1-b] thiazoles with dialkyl phosphites in acetonitrile is developed using Phen as the ligand and K2S2O8 as the oxidant to give the corresponding C(5) phosphonated products in moderate to good yields with high regioselectivity.217 A Pd(OAc)2-catalysed oxidative ortho-acylation of 2-arylbenzoxazoles and 2- arylbenzothiazoles with toluene derivatives as acyl sources and TBHP as oxidant results in the desired products in moderate to good yields with excellent regioselectivity. A plausible mechanism is proposed.218 152 Organic Reaction Mechanisms 2015

The ligand exchange between Pd(OAc)2 and a hydrogen phosphoryl compound HP(O)Z1Z2 (Z1 = Z2 = R; Z1 = Z2 = OR; and Z1 = R and Z2 = OR) occurs readily in 1 2 presence of PEt3 to produce the trans-Z Z P(O)-Pd(PEt3)2(OAc) (X). A successive ligand exchange reaction between (X) and phenylacetylene generates (phosphoryl)- (alkynyl)palladium complexes, which upon heating produce the corresponding alkynylphosphoryl compounds via reductive elimination reactions. The stereochemistry at phosphorus is retained in these reactions. On the basis of these studies, a palladium-catalysed stereospecific CDC of P-chiral P(O)–H compounds with terminal alkynes is developed, providing an efficient method to prepare the valuable P-chiral alkynylphosphoryl compounds.219 The H2 reductive cyclization of ortho-bromoaryl 𝛼𝛼-ketoamides in toluene to form 3-substituted-3-hydroxy-2-oxindoles in good to excellent isolated yields is investigated using the Pd2(dba)3⋅CHCl3 complex (dba = dibenzylideneacetone) as catalyst in the presence of the chelating phosphine ligand 1,1′-bis(di-iso-propylphosphino)ferrocene ∘ (DiPPF) and Cs2CO3 as base at 80 C. Reactants bearing aryl substituents give uniformly better results compared to reactants with alkyl groups or heteroaryl groups. The study may be viewed as a prelude to intermolecular H2-mediated Grignard-type reductive couplings of organic halides with carbonyl compounds.220 Success has been achieved in the regioselective and stereoselective coupling of allylic boronic esters with a range of different C-, O-, and N-based nucleophiles in DMF using Pd2(dba)3 as the catalyst in the presence of the ligand (2-furyl)3P and 2,6- dimethylbenzoquinone as the oxidant. Studies into the mechanism of the reaction have shown that the key transmetallation step occurs with the retention of stereochemistry, since overall inversion is observed.221 Rapid and selective formal hydrogenolysis of aliphatic ester RC(O)O–R′ linkages is achieved using a homogeneous Lewis acid (Hf(OTf)4 in combination with a heterogeneous Pd/C catalytic hydrogenation system that mediates rapid, selective, and clean C–O hydrogenolysis to the corresponding carboxylic acids and hydrocarbons. 1H NMR spectroscopic analysis versus an internal standard gives yields of 95% and 97% for cyclohexane and AcOH, respectively. The tandem catalytic system also produces biodiesel from triglycerides in high yield without the co-production of the undesired glycerol. Instead, 222 the C3 backbone is preserved and converted to hydrocarbons and/or oxygenates. A variety of 𝛽𝛽-acetoxylated piperidines are efficiently synthesized with good regio- and diastereo-selectivities in 93% yield from Pd(OAc)2-catalysed intramolecular aminoacetoxylation of unactivated alkenes with H2O2 as oxidant and the crucial di(2-pyridyl) ketone (DPK) as the ligand. DPK promotes the oxidative cleavage of the 223 C–Pd(II) bond by H2O2 at a faster rate than other ligands to give the C–OAc bond. The enantioselective synthesis of chiral sultams is achieved by asymmetric hydrogenolysis of a broad range of racemic aryl- and alkyl-substituted N-sulfonyl- oxaziridines with up to 99% ee in DCM using H2 (100 psi), Pd(OCOCF3)2 as the catalyst, (S,S′,R,R′)-TangPhos (61) as the ligand, and l-camphorsulfonic acid as Brønsted acid. Explicit mechanism studies reveal that the reaction is initiated by N-sulfonyloxaziridine ring opening and proceeds through hydrogenolysis, followed by a dehydration of the tertiary alcohol intermediate and then hydrogenation of the 224 asymmetric imine intermediate. ee 3 Oxidation and Reduction 153

P P H t Bu But (61)

A DFT study has explored the reaction mechanism of Pd(0)-catalysed cycloaddition of alkynyl aryl ethers and alkynes to generate 2-methylidene-2H-chromenes. Specifi- cally, the cycloaddition of alkynyl aryl ethers and 2-butynes catalysed by the Pd(0)/PMe3 complex is focused on (i) the energetics of the overall catalytic reaction pathways, (ii) the structural features of the intermediates and TSs, (iii) the most favourable reaction channel, (iv) the possible reaction channels of hydrogen migration, and (v) the possible pathways for alkyne insertion in this reaction mechanism.225 The kinetics of Rh(III) tetra(p-sulfonatophenyl) porphyrin (TSPPRhIII)-catalysed oxidative N-dealkylation of secondary amines in aqueous solution with O2 as the sole oxidant is first order in (TSPPRhIII). The addition of benzaldehyde dramatically increases the reaction TONs by inhibiting catalyst deactivation. A preference for bulkier secondary amines is apparent, and the Hammett constant 𝜌𝜌 has a value of −1.38, suggesting the formation of an iminium ion intermediate in the rate-determining step.226 + The kinetics of hydrogenation of the charged-tagged alkyne [Ph3P(CH2)4C2H] − c 6 + − c [PF6] , catalysed by [Rh(P Pr3)2(𝜂𝜂 -PhF)] [B{3,5-(CF3)2C6H3}4] (P Pr3 = tris- cyclopropylphosphine, PhF = fluorobenzene), is first order in both catalyst2 andH . Alkyne hydrogenation is 40 times faster than alkene hydrogenation. The addition of phosphine causes a spectacular decrease in the rate, suggesting that the reaction does not follow a deprotonation pathway. The oxidative addition of H2 to the alkyne (or alkene)-bound complex is proposed to be the turnover-limiting step.227 A stereochemically flexible diastereomeric Rh(I) catalyst with a tropos′ 2,2 -bis (diphenyl phosphino) biphenyl ligand (62) is developed that provides access to both enantiomers of an asymmetric hydrogenation reaction solely by changing the temperature. Thus, the asymmetric hydrogenations of prochiral (Z)-𝛼𝛼-acetamidocinnamates and 𝛼𝛼-substituted acrylates produce each enantiomerically pure compound in high yield with constant high enantioselectivity over time. The stated Rh(I) catalyst produces (R)- phenylalanine derivatives in enantiomeric ratios of up to 87:13 (R/S) at low temperature

Aux-O Ph P P Ph O-Aux Aux-O Ph P P Ph O-Aux

Ph + Ph − Ph + Ph − Rh BF4 Rh BF4

(RaxSS)-3 (62) (SaxSS)-3 154 Organic Reaction Mechanisms 2015 and up to 3:97 (R/S) of the corresponding S enantiomers after re-equilibration of the 228 same catalyst at elevated temperature. ee 3-Phenoxybenzoic acids undergo intramolecular dehydrogenative ArH/ArH coupling at the ortho-position to produce dibenzofuran-1-carboxylic acid derivatives (X) selectively. The reaction in DMF is catalysed by [Cp*Rh(MeCN)3][SbF6]2 using Cu(OAc)2 H2O as oxidant under N2. There is significant increase in the yield of X on adding K2CO3 and PivOH. It is also shown that the remaining carboxylic group can be utilized for constructing a further fused ring system. Further, it is shown that [RhCl(cod)]2 has the same catalytic reactivity as [Cp*Rh(MeCN)3] [SbF6]2. Related tetra- and penta- cyclic molecules can also be readily constructed by the present procedure. A reaction mechanism involving 1,4-rhodium(III) migration is proposed.229 DFT calculations on the mechanism of [(Cp*RhCl2)2]-catalysed C–H activation/cyclization of 2-acetyl-1- arylhydrazines with alkynes giving indoles with the hydrazine moiety acting as the internal oxidant indicate that the combined processes of concerted metallation deprotonation (CMD) and alkyne insertion contribute to the overall rate-determining step. The N–N bond cleavage step is examined in detail to understand how the internal oxidant interacts with the metal centre to facilitate the catalytic reactions. The factor influencing regioselectivity is also studied. How different types of substrate (alkynes vs alkenes), internal oxidants (–NH(NHAc) vs –NH(OAc)), and catalytic cycles (Rh(III)/Rh(I) vs Rh(III)/Rh(V)) influence the reaction mechanisms is also discussed.230 An efficient method for the direct ortho-olefination of acetanilides with acrylates and aryl alkenes via [Cp*RhCl2]2-catalysed internal oxidative C–H activation based on hydroxyl as directing group and oxidant in the presence of AgSbF6 and NaOAc as additives in 1,4-dioxane is described. The coupling is more effective for substrates bearing electron-withdrawing substituents than for those bearing electron-donating groups; up to 82% yield has been achieved.231

Cp* Rh−

Me N N+

(63)

An efficient [Cp*RhCl2]2-catalysed C–H activation/annulative coupling of aminopy- ridines with alkynes in 1,2-DCE/PhMe (5:1) using Ag2CO3 as the oxidant and AgSbF6 as an additive to sequester chloride anions has been developed to synthesize 7-azaindole in 74% yield. The reaction is highly regioselective and tolerates various functional groups, permitting the construction of various 7-azaindoles.232 Results of DFT calculations on the mechanism of [RhCp*Cl2]2-catalysed redox-neutral C–H activation of pyrazolones with 1,2-diphenylethyne indicate that (i) the methylene C–H 3 Oxidation and Reduction 155 activation takes place prior to the phenyl C–H activation, (ii) the N–N bond cleavage is realized via Rh(III) → Rh(I) → Rh(III) rather than via Rh(III) → Rh(V) → Rh(III), and (iii) the zwitterionic Rh(I) complex (63) is a key intermediate in promoting the N–N bond cleavage. The rate-determining step is Rh(III) → Rh(I) → Rh(III), which results in the N–N bond cleavage, rather than the alkyne insertion step.233 The ON/OFF reversible switch of the synthesized [Rh(Aza-CrownPhos)2-(NBD)]BF4 catalyst (64), where NBD = norbornadiene, is thoroughly investigated in the asymmetric hydrogenation of dehydroamino acid esters modulated by host–guest interactions. The catalytic activity is turned ON by using alkali metal cations as the trigger for full conversion with excellent enantioselectivities (up to 98% ee). In the OFF state, the catalyst is almost inactive (conversion <1%) because of the formation of an intermolecular sand- 234 wich complex by two aza-crown ether moities and the cationic rhodium metal centre. ee

+ O O O

O N O − BF4 O P O

O P O N O

O O

(64)

An efficient synthesis for− ( )-cis-𝛼𝛼- and (−)-cis-𝛾𝛾-irone in ≥99% diastereomeric and enantioselective ratios is reported by following two simple synthetic pathways diverging from a common epoxide. The diastereoselectivity of the key Wilkinson’s hydrogenation is supported by a detailed DFT modeling study of the geometry of the 2 rhodium 𝜂𝜂 complexes involved in the diastereodifferentiation of the prostereogenic double bond faces.235 de Asymmetric hydrogenation of 𝛽𝛽-secondary-amino ketones to chiral 𝛾𝛾-secondary- amino alcohols in 90–94 % yields, 90–99 % (ee), and with high TONs (up to 2000 S/C; S/C = substrate/catalyst ratio) has been achieved in MeOH, using [Rh((S,S)- BenzP*)(cod)] (65) SbF6 as the catalyst, Cs2CO3 as the base, and ZnCl2 as the activator of the catalyst. A mechanism (Scheme 4) for the promoting action of ZnCl2 on the catalytic system, based on NMR spectroscopy and HRMS studies, is proposed. 156 Organic Reaction Mechanisms 2015

+ Me But t Me But Bu Me P ODCD3 P Cl P Rh Cl− Rh Rh P P P ODCD3 Cl t Me Me But But Me Bu

monomer dimer (65)

monomer ZnCl2

+ Me But P Me But t P Bu P Cl Rh Rh Me P Cl But Me t Rh Bu Me Me P P But

trimer

Scheme 4

The method was used to prepare the chiral pharmaceutical drugs (R)-atomoxetine, (R)-fluoxetine, and (S)-duloxetine in high yields with excellent ee and retention of 236 configuration. ee The turnover frequency of the catalyst [RhCl(mtppms)3](mtppms = monosulfonated triphenylphosphine) in the selective C=C reduction of trans-3-phenyl-2-propenal by H2 − −1 transfer from HCOO in mixed H2O–2-propanol mixtures is 1214 h . The high catalyst activity in the mixed solvent is conducive for transfer hydrogenation of 3,7-dimethyl-oct- 6-en-1-al. Although good to excellent conversions are observed, a useful degree of selectivity in hydrogenation of C=C versus C=O bonds is not achieved. A large part of the observed rate increase in mixed solvent, compared to aqueous solution, is a consequence of complete dissolution of trans-3-phenyl-2-propenal in the co-solvent, whereas increasing rate with increasing 2-propanol concentration is attributed to changes in the solvent structure. A reaction mechanism, based on identification of cis-mer-[H2RhX(mt ppms)3] − (X = HCOO or H2O) as the major Rh(I) species in the reaction mixture, has been 237 suggested. Synthesis of an o-diphenylphosphinophenyl-based C1-symmetric diphosphine series is described, wherein the chirality is solely borne by a single phosphorus 3 Oxidation and Reduction 157 atom. These diphosphines have been screened as ligands in Rh(I)-catalysed asymmetric hydrogenation of activated olefins. This rigid design brought further mechanistic insights into the relationship between steric and electronic factors of the related C2-symmetric ′ ′ 238 P,P,P ,P -tetraarylic CH2CH2-bridged ligands. ee Alkenyl pinacolboronates are obtained from the reaction of aliphatic terminal alkenes with pinacolborane using [Rh(cod)2]BF4 (cod = 1,5-cyclooctadiene) complex as the pre- catalyst with the ligand i-Pr-Foxap (66) in the presence of norbornene, which acts as the sacrificial hydrogen acceptor. The reaction is applied to the one-pot syntheses of aldehydes and homoallylic alcohols from aliphatic terminal alkenes.239

Me O N

P Fe

(66)

5 The electron-deficient 𝜂𝜂 -cyclopentadienyl-Rh(III) complex (67) is a highly active pre- catalyst in acetone for the oxidative sp2 C–H bond olefination of anilides with both activated and unactivated alkenes in 51–85% yields. Deuterium KIE revealed that the C–H bond cleavage step is turnover-limiting. The use of [Cp*RhCl2]2 in place of (67) showed no catalytic reactivity against olefination with unactivated alkenes.240

Me CO2Et

Me Me Cl * EtO2C Rh Cl 2 (67)

The accelerating effect of phosphine ligands on the rate of [RhCl(cod)]2-catalysed dehydrogenative silylation and germylation of unactivated C(sp3)–H bonds is described. The reactivity of the phosphine ligand is affected by its steric and electronic nature. Bulky and electron-donating (R)-DTBM–SEGPHOS (68) is most effective in facilitat- ing dehydrogenative silylation of C(sp3)–H bonds while suppressing the competitive hydrosilylation of 3,3-dimethyl-1-butene, a hydrogen acceptor. The proper choice of phosphine ligands also enables the unprecedented enantioselective silylative desym- 3 241 metrization as well as the dehydrogenative germylation of C(sp )–H bonds. ee 158 Organic Reaction Mechanisms 2015

OMe But But But OMe O But P O But O P

O OMe But But But OMe (68)

A detailed mechanistic analysis of dynamic kinetic resolution of allylic sulfoxides using asymmetric [Rh((S,S)-Ph-BPE)]BF4-catalysed hydrogenation, based on both experimental and theoretical methods, revealed Rh to be a tandem catalyst that promoted both hydrogenation of the alkene and racemization of the allylic sulfoxide. In such cases, a change in loading of the catalyst does not control the relative rates of racemization and hydrogenation. Hence the catalysis of hydrogenation of racemic (69) is carried out in MeOH at low pressure of H2 so that the rate of racemization relative to the rate of hydrogenation is increased. The enantioenriched aryl(propyl)sulfoxide (70) 242 is then obtained in 92% yield and 88% ee ((S,S)-Ph-BPE = 71). ee

O− H P O− S+ S+ Ar Ar H P

(69) (70) (71)

Optically active 3-amino-1,2-propanediol derivatives are synthesized in up to 99% ee by oxidizing the product obtained from the asymmetric diboration of N-acyl-protected allyl-amines (substituted imides, amides, and carbamates) in the presence of THF, NaOt-Bu, and B2pin2, and chiral Rh[bis(oxazolinyl) phenyl] complexes (72) as catalyst (X = i-Pr, Y = H; X = Bn, Y = H; X = Ph, Y = H and X = i-Pr, Y = Me), with the oxidant 243 NaBO3⋅4H2O. ee DFT calculations are made on the catalytic cycle for the heterolytic cleavage of H2 and hydrogenation of N-benzylidenemethylamine in THF catalysed by the complex [TpMe2 Rh(bdt)Me CN)](TpMe2 = hydrotris(3,5-dimethyl pyrazolyl)borato ligand, 3 Oxidation and Reduction 159

X O Y N OAc

Rh OH2 OAc Y N O X (72) bdt = 1,2-C6H4S2)(73). The results show that the reaction proceeds via an ionic mechanism comprising of three steps: (i) the addition of H2 to the Rh centre, (ii) protonation of imine forming iminium cation, and (iii) the hydride transfer process. The heterolytic splitting of dihydrogen is the rate-determining step. Protonation of imine follows the formation of a Rh(H)–S(H) moiety. The favoured path for the formation of iminium cation is the heterolytic cleavage of H2 at the Rh–S bond, yielding the hydride thiol, and then the transfer of the proton on S to the N atom of the imine.244

Me Me N N Me H B Me N N N N Rh S

Me N S Me

Me (73)

A mechanistic study has found that trans-hydrogenation of internal alkynes, catalysed by [Cp*Ru(cod)Cl]-complexes, competes with a pathway in which both H atoms of the H2 molecule are transferred to a single alkyne C atom of the substrate while the second alkyne C atom is converted into a metal carbine. DFT calculations indicate that the trans-alkene and the carbine complex originate from a common metallacyclopropene intermediate; a p-hydrogen-induced polarization NMR study 245 confirmed that both transferred H atoms came from the very2 sameH molecule. Synthesis of ethers by hydrogenation of various aliphatic and aromatic lactones, linear esters, and the challenging aromatic and aliphatic esters is accomplished in good to excellent yields using a Ru complex, formed in situ from Ru(acac)3] and 1,1,1-tris(diphenylphosphinomethyl)ethane (triphos) as catalyst and aluminum triflate (Al(OTf)3) as the co-catalyst. The straightforward reductive coupling of carboxylic 160 Organic Reaction Mechanisms 2015 acids with alcohols to give ethers is also realized. The in situ formed catalyst is reusable several times without any significant loss of activity. The reactivity order is 246 𝛾𝛾-lactones > aliphatic 𝛿𝛿-lactones > aromatic 𝛾𝛾-lactones ≫ linear esters. The highly selective [{RuCl2(p-cymene)}2](74)-catalysed C–H arylation of indoles and pyrroles is accomplished by using boronic acids in i-PrOH with Cu(OAc)2⋅H2O as oxidant and the additive AgSbF6. The reaction tolerates a wide range of functional groups, including aryl iodides and tryptophan derivatives. New indole-based ruthenacy- cles are described and their role in the mechanism is investigated. Mechanistic studies suggest that the on-cycle intermediates do not possess a para-cymene ligand and that the on-cycle metallation occurs through an electrophilic attack by the Ru centre.247

Me Cl Cl Me Me Ru Ru Cl Cl Me Me (74)

The [RuCl2(p-cymene)]2-catalysed stereo- and chemo-selective cross-coupling reaction of two different acrylates in 1,4-dioxane in the presence of AgSbF6, Cu(OAc)2⋅2H2O for the synthesis of a variety of highly functionalized (Z,E)-muconate derivatives in 67% yield with good stereo- and chemo-selectivities is achieved. Ele- vation of the temperature leads to a remarkable decrease in the selectivity, whereas lowering the temperature reduces the reaction efficacy. Coordination of the Ru complex with the weakly directing ester group is critical for high stereoselectivity in this transformation. The substituent on the 𝛼𝛼-position of acrylate influences its reactivity 248 and chemoselectivity. de The dearomatizing spiroannulation reaction of 2-arylphenols with internal alkynes in t-Am OH to the desired spirocyclic product in 70% yield with high regioselectivity, catalysed by [RuCl2(p-cymene)2], is achieved using Cu(OAc)2 as the oxidant and ∘ K2CO3 as the base at 140 C. The transformation is realized by a phenol-directed C–H activation, migratory insertion of the alkyne, and subsequent dearomatization of the phenolic ring.249 A Ru(II) catalyst, derived from [HClRu(CO) (PPh3)3] and ethylene bis(dicyclohexyl phosphine) (dCype), was evaluated in the presence of the ligand PhMe for the ability to induce reductive coupling by 2-propanol-mediated transfer hydrogenation for obtaining the desired homoallylic amines in 83% yield from the reaction of allenes with hexahydro-1,3,5-triazines with complete branch-regioselectivity.250 A DFT study at the B3LYP level carried out on the [(Cp*)Ru(picolyl-NHC)(CH3CN)] [PF6](75)-catalysed transfer hydrogenation reaction from i-PrOH to acetophenone examined the two mechanisms, namely (i) the inner-sphere and (ii) Meerwein– 3 Oxidation and Reduction 161

Ponndorf–Verley (MPV). Energetic considerations favour the step-wise inner-sphere mechanism. The hemilability of the picolyl group is stated to determine which mechanism the transfer hydrogenation reaction should follow. The effect of agnostic interaction is also discussed.251

Me PF6 Me Me

Me Me N Ru NCMe N N Me

(75)

The ruthenium complex (76) efficiently catalyses the asymmetric hydrogenation of a wide range of 1,5-naphthyridine derivatives in EtOH to give 1,2,3,4-tetrahydro-1,5- naphthyridines in full conversions and up to 99 % ee. This new protocol provides a method for the synthesis of optically pure 1,2,3,4-tetrahydronaphthyridines and 1,5- diaza-cis-decalins, which have been used as rigid chelating diamine ligands for asym- 252 metric synthesis. ee Me Me

Me Me

Me Me TSO2S Ru N OTf NH2

(76)

The in situ formed Ru(II)biscarboxylate complex (77) catalyses the oxidative C–H/ O–H functionalization of benzoic acids with diphenylacetylene in methanol to the corresponding isocoumarins and water, with air or O2 as the oxidant in the absence of co-oxidants. The functionalization proceeds with excellent levels of chemo-, site-, and regio-selectivity under mild reaction conditions. Mechanistic studies reveal the importance of acetic acid in regenerating (76) by reoxidation of Ru(0) complex.253 162 Organic Reaction Mechanisms 2015

Pri Me

Ru RCO2 O O

R (77)

The asymmetric transfer hydrogenation of a wide array of 1-aryl-3,4-dihydro- II 6 isoquinoline derivatives is achieved using a [Ru Cl(𝜂𝜂 -benzene)TsDPEN] complex (78) in combination with a 5:2 HCOOH/Et3N azeotropic mixture as a hydrogen source. This enables the synthesis of the corresponding valuable chiral 1-aryltetrahydroisoquinoline units with high atom economy, broad substrate scope, high isolated yields (up to 97%), and good to excellent enantioselectivities (up to 99% ee). The stereochemical outcome of the reaction is strongly dependent on both the structure of the catalyst and the 254 substituents present on the substrate. ee

Cl Ru NTs

H2N

(78)

The synthesis of rac-[Ru(bpy)2-(OS–R)](PF6) and Δ/Λ-[Ru(bpy)2(OS–R)](PF6) 2+ complexes by treating cis-[Ru(bpy)2Cl2]⋅2H2O or Δ/Λ-[Ru(bpy)2(py)2] with 2-alkylthiobenzoic acid (HOS–R) is described. Their corresponding oxidation products, rac-[Ru(bpy)2(OSO–R)](PF6), Δ-[Ru(bpy)2{(R)-OSO–R}](PF6), and Λ- [Ru(bpy)2{(S)-OSO–R}](PF6), were obtained in yields of 95% with 98% ee using ee m-CPBA as oxidant. During the in situ oxidation with m-CPBA, the Δ metal-centred configuration enantioselectively generates an R-configuration sulfoxide, while the Λ configuration forms an S-configuration sulfoxide. The chiral sulfoxides are obtained in yields of 90% with 83.5–92.9% ee, by treating the corresponding sulfoxide complexes with TFA in CH3CN. It was also shown that the absolute configurations at the ruthenium centres of these complexes are completely retained during the formation of thioether complexes and oxidation in situ to generate sulfoxide complexes255. RuCl2(PPh3)3-catalysed conjugate hydrogenation of various 𝛼𝛼,𝛽𝛽-enones to saturated ketones is carried out in presence of paraformaldehyde, base K2CO3, and 3 Oxidation and Reduction 163

∘ toluene/H2O = 10 (solvent) at 120 C under an atmosphere of argon when the conversion of enones is >99% and the isolated yield of ketone is >95%. The H2 needed for the hydrogenation is generated in situ from H2O and (CH2O)n. This procedure is 256 free from manipulation of the hazardous high-pressure H2. ee The application of Ru complexes (79) and (80), bearing both a pybox (2,6- bis(oxazoline) pyridine) and a monodentate phosphite ligand, as catalyst is described for the asymmetric reduction of N-aryl imines derived from acetophenones. The catalysts show good activity with a diverse range of substrates under H2 as they deliver the amine products in very high levels of enantioselectivity (up to 99%) under both hydrogenation and transfer hydrogenation conditions in isopropanol and t-BuOK. The very similar performance observed under both reaction conditions points to a common active catalyst for the two types of transformations. From deuteration studies, a very different labelling is observed under hydrogenation and transfer hydrogenation conditions, 257 which demonstrates the different nature of the hydrogen source in both reactions. ee

O N O O N O N N N N Ru Ru Cl Cl Cl Cl L P MeO OMe OMe

L = P(OMe)3 and P(OEt)3 (79) (80)

The synthesized cyclopentadienone imidazolylidene Ru(0) complexes are converted into their corresponding cationic hydroxyl- and methoxy-cyclopentadienyl Ru(II) derivatives. Both these complexes are used as selective catalysts for transfer hydrogenation of aldehydes and ketones in refluxing i-PrOH as hydrogen source. The presence of CAN and benzoquinone (oxidizing additives) is necessary to activate the neutral Ru(0) complexes, though cationic Ru(II) catalysts need no such activation. The catalytic activity of the Ru(II) complexes is influenced by the coordinating ability ofthe counterion. The best conversion (>99%) is obtained with the use of cationic complexes having a pyridine-functionalized NHC ligand and CF3SO3. The release of the CO ligand is the key step in the hydrogenation reaction mechanism, and a hydride species is detected at the end of the reaction.258 A comparative study of H/D exchange at the 𝛼𝛼- and 𝛽𝛽-carbon positions of 2-phenylethanol catalysed by a series of Ru complexes versus D2O in the presence of KOH reveals that the catalytic activity of the Ru complexes and the regioselectivity of the H/D exchange reactions between D2O and alcohols are dependent on the auxiliary ligands. Ru–p-cymene complexes, supported by various amine ligands such 6 6 as [(𝜂𝜂 -cymene)RuCl (NH2CH2CH2 NTs)]Cl, (𝜂𝜂 -cymene)RuCl2/NH2 CH2CH2OH, 164 Organic Reaction Mechanisms 2015

6 and (𝜂𝜂 -cymene) Ru{(S,S)-NHCHPhCHPh NTs}, catalyse regioselective deuteration at the 𝛽𝛽-carbon positions, while octahedral Ru complexes, supported by the amine ligands RuCl2(2-NH2CH2Py)(PPh3)2 (2-NH2CH2Py = 2-amino methylpyridine) and RuCl2(NH2CH2CH2NH2)(PPh3)2, catalyse H/D exchange at both 𝛼𝛼- and 𝛽𝛽-carbon positions. RuHCl(2-H2NCH2Py)(PPh3)2 and c,t-RuH2(2-H2NCH2Py)–(PPh3)2 give similar results. The complex RuCl2(2-H2NCH2Py)(PPh3)2 is a better catalyst for the reaction, giving deuterated 2-phenyl ethanol with 88% and 85.5% D. A plausible explanation why the (𝜂𝜂6-cymene)Ru and octahedral Ru complexes supported by amine ligand induce different selectivities in the catalytic H/D exchange reactions is given.259 ′ ′ The mechanism of HRu(bMepi)(PPh3)2 (X)(bMepi = 1,3-bis(6 -methyl-2 - pyridylimino) isoindolate)-catalysed acceptorless alcohol dehydrogenation (AAD) is investigated. An inner-sphere step-wise pathway for proton and hydride transfers with a 𝛽𝛽-H elimination turnover-limiting step is supported by experimental evidence. Selective isotopic labelling experiments combined with catalyst modification demonstrate that a cooperative metal−ligand pathway involving the imine functionality is not necessary for efficient dehydrogenation. An associative pathway involving a highly ordered transition state structure is suggested by the observed activation parameters. Thus, it is proposed that a single PPh3 dissociation event from X generates a coordinatively unsaturated HRu(bMepi)(PPh3) species, which undergoes a proton-transfer equilibrium to generate a transient Ru–(H2) alkoxide species. AAD reactions using a series of

i-PrOH acetone

Ph Ph Ph P S Me Ph P S Me H O CRu Ph CRu S S H Ph O O O (81)

Me Me Me Me

OH O

RR RR

Scheme 5 3 Oxidation and Reduction 165

Ru(b4Rpi)(PPh3)2Cl complexes indicate that the ortho-substituted Me groups of bMepi slightly impede the catalytic activity, and electronic modifications of the pincer scaffold have only minimal effect on the reaction rate.260 The catalyst Ru–WOx shows high catalytic activity for the hydrogenolysis of various phenolic compounds with different functionalities to form arenes selectively under hydrogen atmosphere in water. Preliminary mechanistic studies support the reactions occurring via a direct cleavage of the C(sp2)–O bonds, and the concerted effects of the hydrogenating Ru sites and the Lewis acidic W sites are the key to such an unusual reactivity. The catalyst is applied to the hydrogenolysis of a phenolic mixture extracted from bio-oil, yielding a mixture of arenes.261 Inclusion of triphenylphosphine with the catalyst (81) results in a considerable increase in the catalytic reactivity for the transfer hydrogenation reaction of i-PrOH with ketone. DFT studies on the reaction mechanism (Scheme 5) revealed (i) high reaction barriers for both the dehydrogenation of i-PrOH and the hydrogen transfer, and (ii) PPh3 coordination to the metal, forming a cyclometal- lated complex showing high catalytic activity in the transfer hydrogenation of aromatic as well as aliphatic ketones. Its activity under base-free conditions suggested that the 262 cyclometallation is crucial for the enhanced catalysis. ee 3 3 Ru(𝜂𝜂 -methallyl)2 (cod)L, prepared in situ from Ru(𝜂𝜂 -methallyl)2 and L = (S,S)- (R,R)-PhTRAP (82), catalyses the asymmetric hydrogenation of quinolines in presence of triethylamine (base) and EtOAc (solvent), which selectively takes place on their carbocyclic rings to give 5,6,7,8-tetrahydroquinolines in 97% yield without the formation of 1,2,3,4-tetrahydro-2-phenylquinoline. 8-Substituted quinolines in presence of (82) convert to the chiral 5,6,7,8-tetrahydroquinolines with up to 91:9 er. The unusual chemoselectivity is likely due to the trans-chelating properties of the chiral ligand. Some experimental results suggest that the aromaticity-breaking step is accompanied 263 by the chiral induction. ee

H Me P

Fe Fe

Me H

(82)

An efficient and selective catalytic reduction of a variety of aliphatic, aromatic, and heterocyclic nitriles including adipodinitrile to the corresponding primary amines is achieved using the Ru-Macho-BH complex (83). The best yield of 93% is obtained when 166 Organic Reaction Mechanisms 2015 the hydrogenation is performed at 100 ∘C. Modelling suggests that the reaction follows an outer-sphere hydrogenation mechanism (Scheme 6).264

HBH 3 H H N P Ru R N R NH P H CO

H N P (83) H H2 Ru N P P Ru H CO P H CO

H H H NH R NH R 2

Scheme 6

An efficient method for the synthesis of chiral ferrocenyl alcohols2 byRuCl [(S)-Xyl- SunPhos]-[(S)-Daipen]-catalysed asymmetric hydrogenation of aliphatic and aromatic polyfunctionalized ketones, including 𝛼𝛼-/𝛽𝛽-keto acid derivatives, is that carried out in i-PrOH with t-BuOK as the base under H2. The corresponding alcohols are obtained in quantitative yield and up to 99.8% ee and TON = 5000 specifically from aliphatic acyl ferrocene using the xylyl-substituted ligand (84) which has 3,5-dimethyl groups on the P-phenyl rings of the SunPhos ligand. The presence of the 3,5-dimethyl group significantly enhances the enantioselectivity.265

Me Me Me Me OMe

Me P

Me Me NH2 P Me Me Me Me Me NH2 OMe Me Me (84) Daipen 3 Oxidation and Reduction 167

CO2 H N H NHC Ru NHC H Ru2 H C H O N hydrogenolysis H Ru4* NHC Ru NHC H C HDBU+ HCOO− O H C O DBU O H2

N DBU NHC Ru NHC Ru4-H 2 H C H O H N HDBU+ HCOO− HCOO− NHC Ru NHC H H 2 H C O O N O metal-ligand Ru4 H NHC Ru NHC cooperation O H C H O H C Ru1-H2 N CO2 N O NHC Ru NHC NHC Ru NHC

H C Ru1* H C Ru3 H2 O O

Scheme 7 168 Organic Reaction Mechanisms 2015

DFT calculations, complemented by NMR spectroscopy and kinetic experiments, related to the cooperative behaviour of the dearomatized Ru−CNC* complex (Ru1*) towards H2 and CO2 activation, are indicative of the much higher reactivity of Ru1* towards the ligand-assisted activation of both H2 and CO2 in comparison to that of the structurally related phosphine-based Ru–PNP complex. Heterolytic dissociation of H2 by Ru1* results in the bis-hydrido complex Ru2, which is active in CO2 hydrogenation. An increase in the H2/CO2 ratio effectively suppresses the deactivation path, which results in a stable and rather high catalytic performance of Ru–CNC complex. Both cooperative (metal–ligand cooperation) and non-cooperative (hydrogenolysis) paths for the catalytic reaction by the bis-hydrido Ru−CNC catalyst Ru2 are considered. The catalytic role of the cooperative [1, 4]-CO2 adduct Ru3 is also evaluated. Scheme 7 266 represents the proposed mechanism. de The synthesis of Ru complexes bearing the carbodicarbene-type ligand ‘cyclic bent allene’ (CBA) from the common precursor RuHCl(CO)(PPh3)3 is described. These complexes are superior in their catalytic activity compared to known ruthenium hydrido- carbonyl phosphine complexes. The complex RuH(OSO2CF3)(CO)(SIMes)(CBA)(85), (SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4-5-dihydroimidazol-2-ylidene) in particular, is highly active in the hydrogenation catalysis of both functionalized and non- functionalized olefins in2 CH Cl2 at room temperature even at low loadings as well as 5 267 in diastereoselective reductions with TON = 1.28 × 10 and yields >90%.

Me Me Me Me N N Me N N Me O O H Me Ru Me Me Me TfO CO SIMes SIMes (85)

+ − The complex [(C6H6)(PCy3)(CO)RuH] BF4 (86) catalyses the hydrogenolysis of carbonyl compounds to yield the corresponding aliphatic products in high yield with high chemoselectivity towards the carbonyl reduction over alkene hydrogenation under environmentally sustainable conditions. The kinetic and mechanistic analyses reveal two distinct pathways that are guided by the electronic nature of the Ru catalyst. The Ru catalyst with an electron-releasing phenol ligand facilitates the hydrogenolysis through concerted H2 addition, while the electron-deficient catalyst acts through stepwise bind- 268 ing and activation of H2 and electrophilic hydrogenolysis of the alcohol substrate. ee Catalytic reactivity of Ru(II) complexes with monotosylated 1,3-diamines is evaluated in the asymmetric transfer hydrogenation of acetophenone and other aryl ketones in the presence of water and HCOONa as a hydrogen donor. The complex (87) is the catalyst of choice, as it is the most efficient in terms of the reaction rate, achieved yield, and 3 Oxidation and Reduction 169

− BF4 Ru+ H PCy3 CO (86) enantioselectivity. The activity of the catalyst is dependent on the hydrogen donor and the solvent as well as the electronic and steric properties of the substrate. The 1,3-diamines are synthesized using a biotransformation reaction employing the fungus Curvularia lunata.269

Me Me Me Cl Ru H2N NHTs

(87)

The ligand (4-phenylquinazolin-2-yl)methanamine is synthesized in high yield from glycine in a few steps. The activity of the complex (88), obtained as the major product by refluxing the ligand with2 RuCl (PPh3)dppb (dppb = 1,4-bis(diphenylphosphino)butane in presence of Et3N and i-PrOH, is studied in the transfer hydrogenation of acetophenone and its derivatives in presence of 2-propanol and NaOH under mild reaction conditions 5 −1 270 with excellent conversions of up to 99% and high TOF values of up to 1.188 × 10 h . de

Cl Cl Ru N PH H2N

(88) 170 Organic Reaction Mechanisms 2015

High yields, selectivity, and functional group compatibility are achieved in an efficient protocol for the E-selective transfer semi-hydrogenation of electron-neutral alkynes to the corresponding E-stilbene in 98% isolated yield with excellent chemo- and stereoselectivity in dimethoxyethane using the Ru complex (89) in presence of HCOONa and HCOOH. Step-wise transfer of both the hydride and the proton of the formic acid to the substrate is the suggested mechanism. The protocol can be applied to the synthesis of monodeuterated alkenes by simply applying a HCOOH/HCOONa/D2O mixture as a hydrogen source.271

H OH HO H OC

P Ru P OC Cl

(89)

− The kinetics of OsO4-catalysed oxidation of l-arginine to 𝛼𝛼-keto acid by IO4 in − alkaline medium is zero order in arginine, first order in 4OsO , second order in IO4 , and fractional order in OH− ions.272 The kinetics of similarly catalysed oxidation of sulfadiazine (4-amino-N-(2-pyrimidinyl) benzenesulfonamide (SD) by CAT in alkaline − medium is first order in both CAT and OsO4 and an order less than 1 in SD and OH ions. The catalysed reaction is about nine-fold faster than the uncatalysed reaction.273

Oxidation by Compounds of Non-metallic Elements Sulfur and Boron The optimized reaction condition for the syn-dioxygenation of indenes and dihydronaph- thalenes to produce 1,3-dioxolanes is to add powdered oxone (potassium peroxomono- sulfate) to a stirred slurry of NaHCO3 and the indene in a mixture of acetone + ethyl acetate + water. The yield of 1,3-dioxolane from the simple indene is 82%. Preliminary control experiments reveal that the current dioxygenation is not due to trace metal present in the reagents used and also that epoxide may not be involved as an intermediate.274 The kinetics and mechanism of 𝛽𝛽-cyclodextrin-catalysed oxidation of glutamine (Glt) by oxone is first order in Glt and oxone. Variation of the ionic strength and the solvent polarity has negligible effect on the rate. The constant for the interaction of 𝛽𝛽- cyclodextrin and glutamine is 72.76 × 103 M−1.275 The kinetics of oxidation of [Ni(II)(H2L1)](ClO4)2,(H2L1 = 3,8-dimethyl-4,7-diaza- 3,7-decadiene-2,9-dione dioxime) and [Ni(II)(HL2)]ClO4,(H2L2 = 3,9-dimethyl-4,8- 3 Oxidation and Reduction 171

2− diaza-3,8-undecadiene-2,10-dione dioxime) by S2O8 (PDS) in aqueous media are first + 2+ order in the complexes and PDS. The H dependence for [Ni(II)(H2L1)] is complex over the pH range 4.98–7.50, while reaction of [Ni(II)(HL2)] is pH-independent over the range 5.02–7.76. In both cases, kobs decreases with increasing ionic strength, but this 2+ + 276 is more pronounced for [Ni(II)(H2L1)] than for [Ni(II)(HL2)] . de Studies on the diastereoselective oxidation of 1-thio-𝛽𝛽-d-glucopyranosides with organic peracids indicate that the sense (usually the major isomer has an S absolute configuration at sulfur) and the degree of stereochemical outcome of the oxidation are very much dependent on the presence of the sulfur substituent and on the group protecting C(2)–OH. Thus, mesylation of the C(2)–OH allows the formation of the sulfinyl glycoside with RS absolute configuration at sulfur as the major isomer. In the case of thioglycosides with a bulky aglycone, the mesylation of C(2)–OH has a significant effect on the stereochemical outcome of the oxidation, affording the usually less favoured RS sulfoxide as a single diastereoisomer. The absolute configuration of the final sulfinyl glycosides was established by NMR and X-ray crystallography.277 + The kinetics of oxidation of substituted 5-oxoacids by H2BO3 ion in AcOH–H2O is + + first order both in 5-oxoacid2 andH BO3 ion and second order in H ion. The reaction rate increases on lowering the dielectric constant and by electron-releasing substituents, but the rate decreases by electron-withdrawing substituents on the aromatic ring. The order of reactivity is p-methoxy ≫ p-Me > p-Ph > –H> p-chloro > p-bromo > m-nitro. + The oxidation is faster than the H2O2 oxidation. H2BO3 reacts with the enolic form of the oxo-acid in the rate-determining step, giving the cyclic boronate ester, which decom- 278 poses to carboxylic acid by C–C cleavage. de DFT calculations on the mechanism of the Lewis acid C6F5(CH2)2B(C6F5)2, catalysed hydrogenation of 2-phenyl-6-methylpyridine, have shown that there are five plausible pathways: (i) the formation of a FLP by Lewis acid, generated from hydroboration of the alkene and pyridine, (ii) activation of H2 by FLVP to give an ion pair intermediate, (iii) formation of the 1,4-dihydropyridine as the result of intramolecular hydride transfer from the boron atom to the pyridinium cation in the ion pair intermediate, (iv) hydrogenation of the 1,4-dihydropyridine by the FLP to form 1,4,5,6-tetrahydropyridine (X), and (v) hydrogenation of X by the FLP to form piperidine. The hydrogenation processes (iv) and (v) follow a similar pathway involving four steps: (a) proton transfer from the pyridinium moiety to the substrate, (b) dissociation of the newly generated pyridine, (c) formation of the hydrogenated product by hydride migration from the hydridobo- rate moiety to the protonated substrate, and (d) regeneration of the free borane from the release of the hydrogenated product. The rate-limiting step is the proton transfer in the second hydrogenation step.279 An alkene-promoted HB(C6F5)2-catalysed hydrogenation of alkynes to give both Z- and E-alkenes in high yields with excellent stereoselectivities is achieved. Z-Alkenes are produced directly by metal-free hydrogenation whereas E-alkenes are generated through an isomerization of the Z-alkenes, which is facilitated by HB(C6F5)2. The experimental and theoretical studies for the mechanism indicate that interactions between H and ee F atoms of the alkene promoter, borane intermediate, and H2 play an essential role in 280 promoting the rate-determining hydrogenolysis reaction. de The hydrogenation of a wide range of 2,3-disubstituted quinoxalines with H2 to 1,2,3,4-tetrahydro-2,3-dimethyl quinoxaline is achieved in 80–99% yields with 172 Organic Reaction Mechanisms 2015

excellent cis selectivity using the borane catalyst B(C6F5)3 or B(p-HC6F4)3 to produce the desired tetrahydroquinoxalines. Significantly, the asymmetric reaction employing chiral borane catalysts generated by the in situ hydroboration of chiral dienes with HB(C6F5)2 under mild reaction conditions is also achieved with up to 96% ee, and represents the first catalytic asymmetric system to furnish optically active 281 cis-2,3-disubstituted 1,2,3,4-tetrahydroquinoxalines. ee The spiroborate ester (90) is used as a highly efficient chiral catalyst in the borane reduction of acetophenone and other aryl alkyl and halogenated ketones. The corresponding alcohols were obtained in high yields and with enantioselectivities up to 98% ee. The amino alcohol moiety of the spiroborane molecule is the predominant factor affecting the enantioselectivity of the reduction. The selectivity of the borane reduction of prochiral ketones catalysed by spiroborate esters depends on the order and the rate of 282 the reagent addition, the solvent, and the borane source. ee O O B− N + O H

(90)

1,2,3-Triazolylidene-based mesoionic N-heterocyclic carbene (MIC) boranes are synthesized from the corresponding 1,2,3-triazolium salts, base, and borane. Borenium ions, obtained by hydride abstraction, serve as catalysts in mild hydrogenation reactions of imines and unsaturated N-heterocycles at ambient pressure and temperature. When the MIC-based systems are isosteric with the corresponding NHC-derived borenium ions, they are more active.283 The kinetics and mechanisms of the triarylborohydrides with benzhydrylium ions, iminium ions, quinone methides, and Michael acceptors are investigated, and their nucleophilicity is determined and compared with those of other hydride donors. The hydri- doborate salts are synthesized from triaryl boranes, ammonium or phosphonium halides, and triethylsilane in high yield under mild conditions.284 B(C6F5)3-catalysed transfer hydrogenation of 1,1-disubstituted alkenes with cyclohexa-1,4-dienes in 1,2-F2C6H4 involves the formation of a Brønsted acidic − Wheland complex and [HB(C6F5)3] . A sequence of proton and hydride transfers onto the alkene results in 90% conversion and 64% yield of the alkane product. Undesired reactions such as the formation of carbenium ion intermediates, which lead to cationic hetero- or homo-dimerization, are largely suppressed by using 1,3,5-trisubstituted cyclohexa-1,4-diene as the dihydrogen source. Computationally analysed reaction pathways lead to a mechanistic picture that is in complete agreement with the experimental observations.285 The synthesis, characterization, and reactivity of a new type of borenium cation employing a naphthyl bridge and a strong P → B interaction are described. The cation reacts with H2 in the presence of Pt-Bu3 but also on its own. The mechanism of the reaction between the borenium cation and H2 in the absence of Pt-Bu3, investigated using D-labelling experiments and DFT calculations, imply the side-on coordination of H2 to the B centre, followed by heterolytic splitting and concomitant cleavage of the 3 Oxidation and Reduction 173

B–Mes bond. The molecule also reacts with 3-hexyne through a syn-1,2-carboboration reaction.286 Solutions of ansa-aminoborane (91), an FLP with the smallest possible Lewis acidic boryl site (BH2) and a bulky 2,2,6,6-tetramethylpiperidine as the basic component, split H2 in a fast and reversible process producing the adduct (92) at moderate pressures and temperatures. The thermodynamic and kinetic features, as well as the mechanism of this reaction, studied by variable-temperature NMR spectroscopy, spin-saturation transfer experiments, and DFT calculations, provide comprehensive insight into the nature of (91).287

Me Me Me Me N N+ Me H Me Me Me H − BH2 B H H (91) (92)

A highly active and selective process for the deoxygenation of terminal 1,2-diols at the primary position, to form chiral 2-alkanols in nearly perfect enantiomeric excess, is initiated by triphenylboron as catalyst in the presence of Ph2SiH2 and Et3SiH via the transient formation of a cyclic siloxane. The utility of the method is illustrated by a short 288 synthesis of the anti-inflammatory drugR ( )-lisofylline (93). ee OH O Me N Me N

O N N Me (93)

Asymmetric reduction of a variety of t-butanesulfinyl ketimines by an N-heterocyclic carbene borane based on a triazole core (94) is achieved in the presence of p-TsOH and ∘ methanol in yields up to 88% and up to 94% de at −10 C. Thus NHC–BH3 is a valuable 289 alternative reducing reagent. ee Me N - + B H3 N Me (94)

The effect of additive BF3 on oxazaborolidine-catalysed enantioselective reduction of aromatic trifluoromethyl ketones, including para-substituted biphenyl trifluoromethyl 174 Organic Reaction Mechanisms 2015 ketones, in THF is to enhance the enantioselectivity (up to 90% ee) and yield ( up to ee 91%). The catalyst (95) is generated in situ from the chiral lactam alcohol (96) and borane.290

N O B N OH O H (95) (96) Reductive ring opening of aza-bridged pyridoazepine (cyclic N,N-acetal) systems forms the desired C–N1 cleavage product 3-(1-benzylpyrrolidin-2-yl)-N-methylpyridin- 2-amine in 89% yield on hydrogenation with sodium cyanoborohydride in acetic acid; aromatic fused azepine, the C–N2 cleavage product, is not detected. Selective control of the reaction pathways is determined by the electronic nature of the substituents on the two nitrogen atoms. Electron-donating or electron-neutral substituents on the bridgehead nitrogen regioselectively favour C–N1 bond cleavage; iminiums are the likely key intermediates for the two pathways proposed. The reductive cleavage provides a convenient method to access novel 2-aminonicotine and pyrido[2,3-b]azepine derivatives.291 A novel BF3/ether reductive system for diphenylmethanols and their ether and ester derivatives is described that presents a metal-free strategy to afford the corresponding alkane products in good to excellent yields. The addition of extra water is beneficial for the reduction process, and D-labelling experiments determined that the reductive hydrogen is generated from ethers. The protocol is attractive and practical because of its favourable safety profile, easy handling, and environmentally benign nature.292

Halogens The stoichiometry and kinetics of reaction between isonicotinic hydrazide (INH) and the OCl− ion were studied at pH > 10 in aqueous medium. The oxidation product in excess of OCl− ion is isonicotinic acid, whereas when isoniazid is in excess, 2-(4-pyridinylcarbonyl)hydrazide is the major product. Under all conditions, the rate-determining step of the overall reaction is the rapid bimolecular reaction between the neutral from of isoniazid and the anionic hypochlorite ion.293 Oxidation of pyruvic acid by hypochlorous acid is studied in the pH range1.0–11.0. The main reactive species are the pyruvate ion and HOCl. The reaction is second order in both reactants. The relatively large negative entropy of activation is consistent with an oxygen- atom-transfer mechanism. DFT calculations support this conclusion by predicting a concerted rearrangement of the activated complex, which includes the reactants and the solvent water molecule. It is also confirmed that the hydration of pyruvic acid hasa significant contribution to the observed kinetics under acidic conditions. The hydration is a proton-catalysed process, and the pseudo-first-order rate constant is interpreted by considering the protolytic and hydration equilibria of pyruvic acid. The rate constants were determined for the non-catalytic and the proton-catalysed paths.294 3 Oxidation and Reduction 175

The reactions of dichloroisocyanuric acid (DCICA) with acetone and 2-butanone in − AcOH–HClO4–H2O, studied in absence and presence of Cl ions, are pseudo zero and pseudo first order in DCICA and first and fractional order in substrate+ andH ions in presence and absence of Cl− ions, respectively. The rate increases with increase in Cl− ion concentration and AcOH composition. The results are interpreted in terms of (i) rate-determining enol formation from the conjugate acid of the ketone (SH+) in the absence of added Cl− ions, and (ii) rate-determining interaction of SH+ with the most effective molecular chlorine species produced by the hydrolysis of DCICA (rather than a rate-determining interaction of enol with chlorine) in the presence of added chloride ions.295 The oxidation of erythritol by CAT, catalysed by Ru(III) in HClO4, in presence of + 296 Hg(OAc)2 is zero order in erythritol and H ions and first order in CAT and [Ru(III)]. Similarly catalysed acidic oxidation of thiamine (THM) by CAT to 4-amino-2-methyl- 4,5-dihydropyrimidine-5-carbaldehyde, and 2-(4-methyl-1,3-thiazol-5-yl)ethanol is first + 2− order in Ru(III), THM, and H ions. Protonated CAT and [RuCl5(H2O)] are the reactive species. The observed rate increases with decrease in the dielectric constant and increase in ionic strength of the medium.297 The alkaline oxidation of the orange-II dye by CAT to 1,2-naphthaqueousuinone and benzenesulfonic acid is first order in CAT and orange-II and of inverse fractional order in OH− ion. The rate is unaffected by the ionic strength of the medium or by the added p-toluenesulfonamide and Cl− ion.298 Oxidation of phenol and o-cresol by CAT in AcOH medium is first order in CAT and zero order in phenol/o-cresol; increase in acid strength increases and decreases the rates of the respective reactions. The energy of activation is more for phenol, which indicates the greater reactivity of o-cresol towards CAT.299 Alkaline oxidation of crotonic acid (CA) to acetaldehyde and glyoxylic acid by CAT, catalysed by Ir(III), is first order in both CAT and CA. The first-order dependence on Ir(III) at lower concentrations tends to zero order at its higher concentrations. The rate increases with OH− but decreases on adding p-toluene sulfonamide.300 The kinetics of oxidation of dipeptide glycylglycine (GG) by CAT in aqueous solution to aldehyde, ammonia, and carbon dioxide is fractional order in [GG] and first order in [CAT]. A Michaelis–Menten-type mechanism is proposed, and the rates are compared with that of the monomer glycine.301 Oxidations of balsalazide (BSZ) by CAT and bromamine-T(BAT) to 2-hydroxy-5-nitroso-benzoic acid and 3-(4-nitroso- benzoylamino)-propionic acid in HClO4 medium exhibit the same kinetic dependence. The reactions are first order in BSZ and fractional order in each oxidant and HClO4. The oxidation of BSZ is about five-fold faster with BAT than with CAT.302 The kinetics of oxidation of butane-2,3-diol by N-chlorosaccharin (NCSA) is first order in the tungstophosphoric acid (TPA) catalyst, NCSA, butane-2,3-diol, and in H+ ion. A negative effect of AcOH is observed.303 The chlorination reactions of 2-oxazolidinone with N-chlorosuccinimide (NCS), HOCl, and t-butylhypochlorite are first order in each reactant and have a complex dependence on the pH. The reactivity order with respect to the chlorinating agent is in the order HOCl > t-BuOCl > NCS. The kinetic results obtained in the formation of the N-chloro-2-oxazolidinone are summarized.304 176 Organic Reaction Mechanisms 2015

The kinetics of oxidation of the drug Losartan potassium [LP] by NCS in HCl medium is fractional order in LP and HCl, first order in NCS, and inverse fractional order in Cl− ion. An increase in ionic strength decreases the rate, but an increase in solvent polarity has the opposite effect.305 Chemical oscillations, with and without the presence of metal ions, are seen during the bromination and oxidation of 4-(N,N-dimethylamino)benzoic acid (DMABA) by acidic bromate. DMABA reacts with bromine to yield 3-bromo-4-(N,N-dimethylamino) benzoic acid, the accumulation of which is probably responsible for the observed long induction time, whereupon its rapid consumption is accompanied by rapid bromide production. Different from the recently reported uncatalysed bromate oscillators, where the inclusion of metal ions such as ferroin and cerium could lead to complex behaviours, here only simple periodic oscillations have been observed in those catalysed systems. The initial presence of cerium and bromide shortens the induction time, probably through the release of bromide ion on reaction with bromo-4-(N,N-dimethylamino) benzoic acid.306 The kinetics of acidic bromate oxidation of neomenthol to menthone is first order both in bromate ion and neomenthol. The order in H+ ion is variable, exceeding 1 only 3 for [H+] > 0.15 mol dm− . The decreasing dielectric constant of the medium retards the rate.307 The kinetics of oxidation of monoethanolamine, diethanolamine, and triethanolamine by N-bromophthalimide (NBP) in the presence of mercuric acetate in aqueous AcOH is first order in NBP and fractional order in substrates. A Michaelis–Menten type mechanism is proposed.308 The potentiometrically studied oxidation of 3-benzoylpropionic acid (BPA) in 50:50 (v/v) aqueous AcOH by N-bromo benzamide (NBB) to the corresponding carboxylic acid is first order in BPA, NBB, and H+ ions. The rate is unaffected by the added benzamide. Other effects such as that of temperature, composition of solvent medium, and added mineral acid are also studied. Protonated NBB is the postulated reactive oxidizing species.309 The micellar-catalysed oxidation of dextrose by N-bromosuccinimide (NBS) is first order in NBS, fractional order in dextrose, and negative fractional order in H2SO4. Added succinimide and Hg(OAc)2 have insignificant effect on the rate, and the roleof anionic and non-ionic micelles is best explained by Berezin’s model.310 Synthesis of a new fluorinated ionic liquid,n 1- -butyl-3-methylimidazolium fluoride ([bdmim]F), and its application as a nucleophilic source of fluoride in an oxidative desulfurization–fluorination reaction for the preparation of difluorinated ethers using NBS as the oxidant are described. The C=S double bond of xanthates and thiocarbon- ates when difluorinated gives rise to small libraries of halogenated ketals and thioketals 311 without the use of HF–pyridine or TBAH2F3 and without any particular precaution. The kinetics of oxidation of aliphatic alcohols by 1-bromobenzimidazole (BBI) in aqueous AcOH in the presence of Hg(OAc)2 is first order in alcohol and BBI and fractional order in H+ ion. The rate increases with the decrease in solvent dielectric constant, indicating ion–dipole interaction. The oxidation of aliphatic alcohols shows a Taft 𝜌𝜌 value of −0.72, suggesting an electron-deficient TS; BBIH+ is the postulated reactive oxidizing species.312,313,∗

∗Authors republished the same article in the same journal. 3 Oxidation and Reduction 177

The mechanisms of oxidation of 1,2-diphenylhydrazine by iodine have been examined using semi-empirical and DFT methods. The oxidation proceeds via two independent pathways. One pathway involves a multi-step chain mechanism; the other mechanism, which is faster, occurs via one-step formation of a ‘cyclic’ activated complex 314 which disproportionates into the products. I2-catalysed controlled synthesis of 1,2-azidoalcohol regioisomers, with 98% diastereomeric ratios in yields up to 92%, has been achieved by vicinal azidohydroxylation of alkenes using DMF and NaN3 as the O- and N-nucleophile, respectively. Regio- and stereo-divergence is attributed to the use of I2 as the oxidant because 2-azido-1-phenylethanol is formed in 90% yield with the use of TBHP as the oxidant in the mixture of DMSO + DMF, whereas 2-azido-2-phenylethan-1-ol is obtained with the use of 50% aqueous H2O2 in 82% yield; a 3:1 mixture of the respective isomers is formed in 78% yield with the use of 70% aqueous TBHP. Mechanistic studies with 18O labelling reveal that DMF is crucial for region-divergence and acts as an oxygen source in this azidohydroxylation 315 reaction. I2-mediated oxidative N–N bond formation is achieved in the presence of KI for the synthesis of a variety of 1,2,4-triazolo[1,5-𝛼𝛼]pyridines and other 1,5-fused 1,2,4-triazoles in yields ≥95% from a wide range of N-aryl amidines in DMSO in the presence of K2CO. The presence of KI successfully suppresses the iodination and other side reactions. The cyclization reaction has a short reaction time and is insensitive to air and moisture.316 de 3 An efficient2 I -DMSO-promoted sp C–N bond formation through oxidative coupling between arylmethylketones and secondary amines under metal-free condition has been applied to access 𝛼𝛼-ketoamides. Mechanistic studies reveal that the C(1)-oxygen atom 317 of 𝛼𝛼-ketoamides is derived from DMSO. A computational study of the mechanism of gas-phase I2 oxidation of d-fructose reveals three TSs, corresponding to three consecutive elementary steps via two intermediates. The enthalpies and activation barriers of the steps are reasonably acceptable and are consistent with the mechanism proposed.318 A metal-free selective C–H homocoupling of meta-hydroxypyridine to 3,3′- dihydroxy-2,2′-bipyridine is obtained in 70% yield with high regioselectivity using phenyliodine(III) diacetate (PIDA) in CH2Cl2 with Cs2CO3 as base additive. The coupling takes place exclusively at the ortho-position with respect to the hydroxypyridine. Comparative control experiments with m-alkoxypyridine suggest that the m-hydroxy group at the pyridine ring plays a key role during the homocoupling reaction. The 3,3′-dihydroxy-2,2′-bipyridine derivatives are widely used as ligands for the coordination of transition metals for many applications.319 Periodate oxidation of vanillin (Van), uncatalysed and catalysed by Ru(III), in alkaline medium is first order in periodate and Ru(III) and less than unit order in Van and OH− ions. The ionic strength and dielectric constant of the medium do not have any significant effect on the rate. The 3− 2+ 320 study suggests that [H2IO6] and [Ru(H2O)5OH] are the reactive species. − The metaperiodate (IO4 ) oxidation of riboflavin (RBF) to lumichrome and 1- acetylglycerol in aqueous acidic medium is first order in both reactants; an inverse dependence on H+ ions is observed over the pH range 1.4–2.6. The rate is inhibited by added Fe2+, probably, due to the formation of a Fe3+–periodate complex which is − less reactive than free IO4 . The deprotonated form of RBF is more reactive than its conjugate acid RFB2+ over the pH range studied. The detection of free radicals indicates 178 Organic Reaction Mechanisms 2015 that periodate acts as one-electron transfer oxidant. An inner-sphere mechanism in which the deprotonated form of RFB bridges the periodate in a step preceding the rate-determining steps is suggested.321

Peracids The 2-iodobiphenyl-catalysed intramolecular aliphatic C–H amination (specifically of 2-cyclohexyl-N-methoxybenzamide to 2′-methoxyspiro[cyclohexane-1,1′-isoindolin]- 3′-one) to 𝛾𝛾-lactam is achieved in hexafluoro-2-propanol with meta-chloroperoxybenzoic acid (m-CPBA) as oxidant under mild reaction conditions in a short time. DFT calculations show that the preferred pathway involves an iodonium cation intermediate and proceeds via a concerted C–H/C–N bonding TS, through hydride transfer followed by the spontaneous C–N bond formation.322 Statistical experimental design, multivariate modeling, and response surface methodology are used to investigate the oxidation of 2,6-dimethoxyacetophenone by m-CPBA. The optimized reaction protocol is used to investigate variously substituted acetophenones. The overall investigation reveals that both the molecular structure of the acetophenone and the experimental conditions had a substantial impact on whether the oxidation reaction follows the oxygen insertion or direct ring hydroxylation mechanism. An improved protocol for the direct aromatic ring hydroxylation is suggested.323 The kinetics of oxidation of aromatic anils in the aniline moiety by m-CPBA in aqueous AcOH is second order in anil and first order in the oxidant; an increase+ inH retards the rate. The kinetic effects of 3 meta- and 5 para-substituents on the anil follow the isokinetic relationship and Exner relationship but not any of the linear free-energy relationships. The Hammett plot exhibits a concave downward curve for the anils with substituents on the aniline moiety.324

Ozonolysis and Ozonation The gas-phase ozonolysis of trans-2,2-dimethyl-3-hexene (22dM3H), trans-2,5- dimethyl-3-hexene (25dM3H), and 4-methyl-1-pentene (4M1P) is investigated in the presence of the hydroxyl radical scavenger. Ozone levels in the reactor are monitored by an automatic analyser while concentrations of alkene and gas-phase product are determined via on-line sampling. Primary carbonyl products are identified, and branching ratios are reported. The yield of a Criegee intermediate is indirectly determined in the ozonolysis of 4M1P. Total yields of the primary carbonyl products are very close to 100%, which is in agreement with the well-known mechanism of alkene ozonolysis. Results of kinetic and product study have been compared with literature reports where available.325 The kinetics and mechanisms of ozone reactions with alcohols, ketones, ethers, and hydroxybenzenes in organic solvents have been studied to determine the influences of the structure, medium, and other reaction conditions. The corresponding thermodynamic parameters are reported, and possible applications of ozonolysis are specified and discussed.326 Kinetics and mechanisms of oxidation of 4-aminotoluene and its acylation derivatives by ozone/air mixtures in glacial acetic acid have been reported. The process of formation of acetaminobenzoic acid by liquid-phase catalytic oxidation of 4-acetaminotoluene 3 Oxidation and Reduction 179 by ozone in the presence of transition-metal salts and their mixtures with potassium 327 bromide has been investigated. DFT study of gas-phase ozonolysis of 𝛼𝛼-pinene ([1S,5S]-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene), 𝛽𝛽-pinene ([1R,5R]-6,6-dimethyl-2- methylenebicyclo[3.1.1]heptane), camphene ([1R,4S]-2,2-dimethyl-3-methylenebicyclo [2.2.1]heptane), and sabinene ([1R,5R]-4-methylene-1-(1-methylethyl)bicyclo[3.1.0] hexane) has considered different O3 attacks on the double bond. The kinetics of O3 additions are influenced by the location of the endo- or exo-cyclic double bond (𝛼𝛼-pinene and 𝛽𝛽-pinene) and the proximity of the methyl groups to the double bond (camphene and sabinene, respectively). The formation of both exo (upward O3 attack) and endo (downward O3 attack) conformers of the molozonides is considered. The relative Gibbs free energy differences do not show significant distinction, and the branching ratios for formation of the exoconformers are greater than 97% for 𝛼𝛼-pinene, 𝛽𝛽-pinene, and camphene, whereas for sabinene the formation of exo- and endo-conformers seems to compete. The kinetic model, based on reversible prebarrier complex formation and conversion into the molozonide, provides better results than the elementary bimolecular reaction model. The canonical variational (CVT) rate coefficients show reasonable agreement with the microcanonical variational rate coefficients, the latter being somewhat smaller. The final results suggest that description of the reaction mechanism for monoterpenes must take account of the role of the prebarrier complex.328 The reaction mechanism for the formation of collisionally stabilized excited Criegee CH2OO* intermediate (having a lifetime of a few seconds) from the O3 + C2H4 reaction is studied using high-accuracy quantum chemical calculations in conjunction with the two-dimensional master equation/semi-classical transition-state theory technique. The calculated product branching ratios are in excellent agreement with experimental results. The intermediate, being very reactive, reacts rapidly with other species in the reaction system (or dissociates thermally to several products within a couple of seconds). As a result, the stabilized Criegee intermediate has not been detected spectroscopically. Finally, evidence suggests that the hydroxyl radical product is mainly formed by a step-wise decomposition of primary ozonide via the singlet biradical intermediate 329 ⋅OOCH2CH2O⋅ and through HOOCH2CHO (hydroperoxy methylformate). Oxida- tion of bilirubin to choletelin, by benzoyl peroxide in dimethyl sulfoxide, takes place through the intermediate products biliverdin and purpurin. A proposed kinetic model is related to the exchange interaction of CH protons of methylene and methine spacers with free radicals in the rate-limiting step with the further destruction of the ‘ridge-tile’ pigment conformation. The mechanism steps are confirmed by quantum-chemical calculations and HPLC. It is found that in organic solvents the end products of bilirubin oxidation are not monopyrrolic derivatives.330 A new and optimized procedure for the allylic oxidation of Δ5-steroids with t-butyl hydroperoxide in the presence of catalytic amounts of N-hydroxyphthalimide (NHPI) under mild conditions has shown excellent regioselectivity and chemoselectivity (functional group compatibility). It is observed that Co(OAc)2 can enhance the catalytic ability of NHPI, resulting in better yields and shorter reaction times. The reaction mechanism and scope of the reaction with a variety of Δ5-steroidal substrates were also investigated.331 Computational chemistry is used to study the thermochemistry, reaction paths, and TS structure energetics for the decomposition of di-t-butyl peroxide (DTBP). The major 180 Organic Reaction Mechanisms 2015 first-step dissociation of DTBP results mainly from RO–OR and R–OOR bond cleavages and several molecular elimination pathways. Over 10 initial reaction paths are identified. Low-barrier or barrierless reaction product sets include two t-butoxy radicals, t-butyl-hydroper oxide, iso-butene, t-butoxy radical, and a hydroxyl t-butyl alkyl radical. Intermediate barrier products include t-butyl peroxy radical, t-butyl radical, t-butyl alcohol, dimethyl oxirane, a methoxy-t-butyl radical, t-butoxy radical, acetone, and methyl-t-butyl ether.332 An experimental/computational investigation strongly supports the reversible formation of cyclohexylidene dioxirane as an intermediate in the oxidation of cyclohexanone with aqueous H2O2. A computational analysis with explicit inclusion of up to two water molecules rationalizes the formation of the dioxirane intermediate via addition of hydroperoxide anion to the ketone but reveals that this species is not involved in the subsequent formation of the Criegee adduct (1-hydroperoxycyclohexanol). This mechanism is operative only in neutral and/or basic conditions. Direct addition of H2O2 to the ketone is favoured over hydrolysis of dioxirane, the latter being in competition with ring opening to carbonyl oxide followed by hydration. However, dioxirane may account for the formation of the bis-hydroperoxide derivative.333 An effective method to synthesize aldehyde in good yield and selectivity is via the selective oxidative C=C bond cleavage of terminal olefins in acetonitrile with H2O2 in association with copper(II) complexed with the macrocyclic ligand 5,7,12,14- tetramethyl-1,4,8,11-tetraaza cyclotetradeca-4,7,11,14-tetraene (LCu, 97) as catalyst. The yield and selectivity of benzaldehyde formation from styrene (chosen as model) increases gradually with increasing pH, and the maximum values are reached at pH 8.0. Aryl olefins with electron-rich substitutents undergo conversion >80% and selectivity >90%, whereas electron-deficient styrene derivatives give lower conversion but higher selectivity (>96%). The catalytic system is also suitable for aliphatic terminal olefins

LCu

H O O H RCHO + H2O H2O2

• R Me Me HC LCu–OOH• LCu N N OOH II Cu MeOH N N Me Me (97) LCu R • OOH R H O C 2 R Me

• HOO–CuL

Scheme 8 3 Oxidation and Reduction 181 such as allylbenzene and 1-octene but is ineffective towards intramolecular alkenes. Scheme 8 depicts a proposed mechanism involving associated radical active oxo species.334 DFT calculations suggest that the H2O2 oxidation of olefins, catalysed by water- soluble Bi salts, occurs via two competitive channels: (i) non-radical epoxidation of the C=C bonds, and (ii) radical hydroperoxidation of the allylic C atom(s) with involvement of the HO⋅ radicals. DFT calculations predict that both epoxidation and hydroperoxidation pathways may be realized concurrently as a result of a rather small difference in the activation barriers. The most plausible mechanism of epoxidation includes (a) 3+ the substitution of a water ligand for H2O2 in the initial aqua complex [Bi(H2O)8] , (b) hydrolysis of the coordinated H2O2, (c) one-step oxygen transfer through a direct 2+ olefin attack at the unprotonated O atom of the OOH– ligand2 in[Bi(H O)5(OOH)] via a TS, and (d) liberation of epoxide from the coordination sphere of Bi. Other concerted and step-wise mechanisms of epoxidation are less favourable. A preliminary experimental study of cyclohexene, cyclooctene, and 1-octene oxidation with the systems Bi(NO3)3/H2O2/CH3CN + H2O and BiCl3/H2O2/CH3CN + H2O indicates the formation of both enol and epoxide/diol products, consistent with the main conclusions of the DFT calculations.335 DFT calculations have clarified the catalytic role of the aqueous complexes 3+ [M(H2O)n] (M = Ga, In, and Sc, n = 6; M = Y, n = 8; M = La, n = 9) in the oxidation of both alkanes and olefins with2 H O2. The olefin reaction occurs via two competitive reaction channels, that is, (i) hydroperoxidation of the allylic C atom(s) via HO⋅ radicals and leading to alkyl hydroperoxides ROOH, and (ii) epoxidation of the C=C bond involving oxygen transfer from the hydroperoxo ligand in an active catalytic 2+ form [M(H2O)n−k(OOH)] (M = Ga, In, Y, La, k = 2; M = Sc, k = 1) to the olefin molecule and leading to epoxides and/or trans-diols. Other concerted and step-wise mechanisms of the epoxidation are less favourable. The nitrate salts are used as catalyst precursors for a reaction of cyclohexene (cycloalkene) with H2O2. Epoxides are the major products with cycloalkane and alkene.336 Four possible mechanisms namely concerted, nonconcerted, ionic, and radical, are considered for the gas-phse oxidation of cysteine with H2O2 in different solvents (THF,H2O, dioxane) and have been explored using quantum chemical calculations. The results favour the ionic mechanism fom the energy point of view. The solvent effect is investigated with explicit solvent and ONIOM models in water. Better agreement with the experimental data is obtained using this method, showing the importance of solvent effects on this kind of reaction. Finally, QTAIM (quantum theory of atoms in molecules) analysis has confirmed the covalent nature of the S–O bond at the TS of the reaction.337 Phthaloyl peroxide oxidation of arenes leads to the synthesis of phenols. Computational study of a newly synthesized 4,5-dichlorophthaloyl peroxide predicted its enhanced reactivity relative to phthaloyl peroxide oxidant, and this has expanded the scope for arene hydroxylation reactions in (CF3)2CHOH. The reaction proceeds through a ‘reverse-rebound’ mechanism with diradical intemediates. This is supported by computational analysis of substituents effects on arenes, isolation and characterization of by-products, and determination of free-energy correlations.338 182 Organic Reaction Mechanisms 2015

The Bu4NI-catalysed coupling reaction of 2-vinylphenols and 4-t-butyl benzoic acid in DCE results in the synthesis of the desired 2,3-dihydrobenzofuran-3-yl 4-(t-butyl) benzoate in 99% yield using t-BuOOH as an oxidant in air. The reaction has high functional goup tolerance. A plausible mechanism based on experiments and literature reports is proposed.339 A novel intramolecular oxidative coupling reaction for the synthesis of benzofuran derivatives via direct C(sp2)–H functionalization for the C–O bond formation is described. The I2-catalysed transformation is carried out in EtOH using TBHP as the oxidant; a catalytic amount of NaN3 as additive plays a crucial role in the coupling process. The yield of benzofuran derivatives is 88% under metal-free conditions. The reaction tolerates a broad substrate scope, and a possible domino Michael addition and an intramolecular oxidative coupling reaction mechanism are also proposed.340 1-Butylpyridinium iodide-catalysed intermolecular sp3 C–N bond formation by direct oxidative amination of benzylic sp3 C–H bonds with benzotriazole (aminating agent) enables the synthesis of N-alkylated azoles in 77% yield using the oxidant TBHP under metal-free conditions. The catalyst can be recycled and reused with similar efficacies for at least eight cycles.341 An efficient methodology for selective benzylic C–H oxidation in a mixture of acetone/water (1:1) is developed using t-butyl hydroperoxide as the oxidant and Fe(TAML)Li (98) as the catalyst. The oxidation of various simple benzylic compounds to the corresponding ketones is carried out with excellent yields and/or selectivity at −10 ∘C. A plausible mechanism for the reaction is proposed.342

O Me Me O N N Me Fe OH2 N N Me Me O O Me

(98)

The detection and identification of the hydroperoxymethyl formate 2(HOOCH OCHO, HPMF) and partially oxidized intermediate species resulting from the oxidation of dimethyl ether is reported. HPMF and its conceivable decomposition products are identified on the basis of observed ionization thresholds and fragmentation appearance energies, interpreted with the aid of ab initio calculations.343 The rate and mechanism of H2O2 oxidation of pyruvic acid to AcOH and CO2 is investigated over the pH range 2–9. The rate constants are determined under pseudo- first-order kinetics (excess of2 H O2). The calculated second-order rate constants follow a sigmoidal shape with pH-independent regions below pH 3 and above pH 7 but increase between pH 4 and 6. Between pH 4 and 9, the results are in agreement with a change from rate-determining nucleophilic attack of the peroxide species HOO− on the 𝛼𝛼-carbonyl group followed by rapid decarboxylation at pH values below 6 to 3 Oxidation and Reduction 183 rate-determining decarboxylation above pH 7.344 Malonoyl peroxide oxidation of an arene in hexafluoroisopropanol (hydrogen-bond donor) leads to the formation ofthe corresponding protected phenol (adduct) in 98% yield. Treatment of the adduct with MeNH2 in EtOH results in theformation of the phenol. An ionic mechanism (Scheme 9) is consistent with the experimental findings and supported by isotopic labelling, Ham- mett analysis, EPR investigations, and reactivity profile studies have been proposed.345

O O

O + O O O + COOH O O− O R R R adduct

MeNH2 in EtOH OH + MeHN COOH R O

Scheme 9

Singlet Oxygen 1 The rate of O2-mediated oxidation of primary and secondary amines is suggested to be directly proportional to the bond dissociation energy (BDE) of the C–H bonds adjacent to the nitrogen atom. Theoretically, the relative BDEs can be estimated by natural bond 1 order (NBO) analysis or by means of JCH coupling constants obtained by NMR spectroscopy. These methods provide an estimation of C–H bond hybridization, and with these data the selectivity can be predicted prior to oxidation. In addition, it is shown that the inherent selectivity can be overridden by significant steric hindrance.346 Evidence for 1 intramolecular transfer of O2 between two acenes, on conversion of (99)to(100), is provided by a combination of UV–vis measurements, NMR experiments, competition reactions, and quenching experiments. Furthermore, the dependence of conformation and temperature is comparable with intramolecular transfer of energy.347

Triplet Oxygen and Autoxidation Green synthesis of benzazole heterocycles from t-BuONa-catalysed direct aerobic oxidative cyclocondensation of readily available alcohols and o-thio/hydroxy/aminoanilines 184 Organic Reaction Mechanisms 2015

H Acceptor 1 O2 H O O O O O Me O Me O O Donor Me Me (99) (100) under air is described. Mechanistic studies reveal that o-substituted anilines promote the initial aerobic alcohol oxidation step.348 A detailed cooperative mechanism, Scheme 10, using aerial O2 as an oxidant, is sug- v − gested to involve two units of the catalyst complex [Re (O)(cat)2] rather than the formation of a previously hypothesized seven-coordinated active oxidant in the oxidation of alcohol. This accords with the experimental as well as the computational model, where the redox-active ligand catechol plays a crucial role in both phases of the catalytic cycle, − as e buffer in O2 homolysis as well as in a dinuclear proton-coupled electron-transfer step, to oxidize the substrate.349

Other Oxidations The metal-free TBHP-mediated carbonyl C(sp2)–H oxidative radical alkynylation of aldehydes with ethynyl benziodoxolones for the synthesis of ynones under metal-free conditions is described. Mechanistic study indicates that this protocol proceeds through a carbonyl C(sp2)–H oxidative radical coupling, and provides a general route to the assembly of diverse ynones with a broad substrate scope and excellent functional group compatibility. In particular, the alkynylation between 1H-indole-3-carbaldehyde and (triisopropylsilyl)ethynyl benziodoxolones in PhCl medium using TBHP as the oxidant afforded the desired ynone in 81% yield.350 Using N-fluorobenzenesulfonimide (NFSI) as the terminal oxidant and organodiselane catalyst, oxidative C(sp3)–H bond acyloxylation affords a diverse array of isobenzofura- nones from simple ortho-allyl benzoic acid derivatives. The synthetic procedure employs mild reaction conditions and gives high chemoselectivity. Mechanistically, the reac- ′ tion is hypothesized to proceed through an allylic selenation/SN2 -substitution domino reaction.351 N-Fluorobis(phenyl)sulfonimide acts as an oxidant and also ‘F’ source for the N- heterocyclic carbine (101 and 102)-catalysed oxidative enantioselective 𝛼𝛼-fluorination reaction of an aldehyde with an alcohol in 1,4-dioxane to give primarily the desired fluorinated product with high ee. The use of NaOAc as base led to a slightly higher ee value and comparable yield.352 An efficient method for the asymmetric 𝛼𝛼-fluorination of azolium enolates, generated from simple aliphatic aldehydes and 𝛼𝛼-chloro aldehydes, is developed for the synthesis of a wide range of 𝛼𝛼-fluoro esters, amides, and thioesters with excellent enantioselectivity using the solvent combination MeOH/CHCl3, NHC precatalyst (103), base K2CO3, 3 Oxidation and Reduction 185

− − − O O O O O O O O O O Re Re O Re O O O O O O O I IV VI

O2 2−

O − O O• − O O O O O O + I O O Re Re O Re O O Re • O O O O O O O O O O O • O • O II III V

Scheme 10 186 Organic Reaction Mechanisms 2015

O O N Cl N Br N + N + N − N − BF4 BF4

Cl Cl Br Br

(101) (102)

O N Me N + N Cl−

Me Me

(103) and NFSI. The suitable basicity not only ensures successful enolization of the acyl triazolium intermediate but also suppresses the non-productive aldol reaction and other side reactions. Pyrazole is employed as an effective acyl transfer reagent in the synthesis of 𝛼𝛼-fluoro amides and thioesters. The highly enantioenriched fluorinated products are shown to be precursors to other useful fluorine-containing chiral building blocks.353 The reaction of 1,4-dilithio-1,3-butadienes (C2H2Li2), as the formal oxidant, with 0 [Ni(cod)2] in the mixed solvent THF/Et2O proceeds smoothly. The Ni in Ni(cod)2 is oxidized to Ni2+ with the simultaneous formation of divalent aromatic dilithionickeloles as dark-red crystalline compounds in good to excellent yields. The dilithionickeloles have a coplanar structure and Ni2+ oxidation state. These results demonstrate that organolithium compounds with 𝜋𝜋-conjugation could be used as oxidants and yet 354 continue to accept extra electrons. Zn(OTf)2-catalysed alkyne oxidation by 2,6- dibromopyridine N-oxide in PhCl (and with the use of 4 Å molecular sieve) forms the product (a variety of isoquinolones and 𝛽𝛽-carbolines) in 85% yield and minimizes the formation of the hydration by-product. Notably, the undesired over-oxidation is completely suppressed. Mechanistic studies and theoretical calculations suggest that the reaction most likely proceeds by a Friedel–Crafts-type pathway.355 The N-heterocyclic carbine-catalysed oxidative coupling of styrenes with aldehydes using NBS/DBU/DMSO (DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene) as an oxidative system under N2 atmosphere enables the regioselective synthesis of 𝛼𝛼,𝛽𝛽-epoxy ketones in moderate to good yields with excellent dr values (>95%). Further, the 𝛼𝛼,𝛽𝛽-epoxy ketones are obtained by the reaction of 𝛼𝛼-bromoacetophenones with aldehydes (Darzens reaction including its asymmetric version) using an NHC catalyst under mildly basic conditions. Mechanistic studies have revealed the preferred reactivity of NHC with alkene/𝛼𝛼-bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.356 The epoxidation of 𝛽𝛽-caryophyllene to caryophyllene oxide is spontaneous in polar aprotic solvents with molecular oxygen under mild conditions with epoxide 3 Oxidation and Reduction 187 selectivities exceeding 70% without the addition of any catalyst or co-reactant. The use of experimental and computational methods favours a mechanism involving electron transfer to molecular dioxygen and subsequent dioxetane formation. The dioxetane then acts as an in situ formed epoxidizing agent. The presence of a one-electron acceptor leads to the selective isomerization of 𝛽𝛽-caryophyllene to isocaryophyllene under 357 nitrogen atmosphere. de ONIOM and DFT calculations of Baeyer–Villiger (BV) oxidation of 4-phenylcyclohexanone with m-CPBA catalysed by Sc(III)–N,N′-dioxide complexes (104) indicate that the rate-determining step is the addition of m-CPBA to the carbonyl group of 4-phenylcyclohexanone. The repulsion between the m-chlorophenyl group of m-CPBA ′ and the 2,4,6-i-Pr3C6H2 group of the N,N -dioxide ligand and the steric hindrance between the phenyl group of 4-phenylcyclo hexanone and the amino acid skeleton ee of the N,N′-dioxide ligand play important roles in the control of the enantioselectivity. The activation barrier is lowered by the activation of the carbonyl group of the ketone by the Lewis acidic Sc(III) centre and proton transfer by m-CBA. The substituents on the amide moiety and the amino acid skeleton of the N,N′-dioxide ligand play important roles in the enantioselectivity of the reaction.358 Epoxidation of a range of N-substituted trans-4-aminocyclohex-2-en-1-ols upon treatment with Cl3CCO2H and meta-chloroperbenzoic aid (m-CPBA) is investigated. A competition between hydroxyl-directed and ammonium-directed patways is observed. Analysis of the diastereoisomeric epoxide mixtures obtained from these reactions indicated the 359 following order of directing group ability: NHBn ≫ NMeBn > OH > NBn2. de Cl Ph 3+ H

O O H O O H R O O N N Sc H O O NH O R Cl N

(104)

The NIS/PhI(OAc)2-mediated diamination/oxidation of various N-alkenyl for- mamidines is reported for the synthesis of bicyclic ureas in CH2Cl2. The results of several control experiments indicate that the oxidation process occurs probably in con- cert with the diamination cyclization. Succinimide generated from the NIS-mediated 188 Organic Reaction Mechanisms 2015

aminoamidiniumation step promotes the PhI(OAc)2-mediated oxidation step.This protocol provides an efficient method for the facile synthesis of fused tricyclic ureas 360 and fused tricyclic thioureas (NIS = N-iodosuccinimide). de The reactivity of the formamides N-methylformamide, acetamide, N-methylacetamide, and propanamide towards OH radicals is measured in terms of rate coefficients, and thereby their atmospheric lifetimes and ultimately their atmospheric fate. Acetamide has the lowest rate coefficient of (0.4–1.1) × 10−12 cm3 molecule−1 s−1. Relative rate coefficients are measured in a smog chamber using on-line mass spectrometry, and the oxidation products’ time traces are fitted using a simple kinetic box model. The mechanism is further evaluated using ab initio calculations to determine the location of the H abstraction and fate of the resultant radicals. N–H abstractions are negligible in each case, but the reactions proceed via C–H abstraction from alkyl groups and from formyl C(O)–H bonds if available. The latter process explains the detection of the toxic compounds HNCO and CH3NCO, which are formed by the ready reaction of the 361 generated radicals with O2. The rate coefficients for the gas-phase kinetics of the oxidation2 ofCH =C(CH3)CH2Cl with OH radicals and Cl atoms have the respective values of (3.23 ± 0.35) × 10−11 and 10 3 1 1 (2.10 ± 0.78) × 10− cm molecule− s− with uncertainties representing ±2𝜎𝜎. Product identification, performed under atmospheric conditions, suggests that chloropropanone is the main degradation product of the decomposition of the 1,2-hydroxy alkoxy radical formed. The reactivity trends and atmospheric implications are discussed.362 An effective In(OTf)3-catalysed oxidative CDC of electronically varied chromenes with 1,3-dicarbonyl compounds and aryl rings in 1,2-dichloroethane is established using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) as the oxidant. Both the C–H alkylation and arylation proceed smoothly at room temperature to afford diverse 𝛼𝛼-substituted chromene compounds in up to 91% yields. Besides these two types of C–H components, simple ketones like cyclohexanones are also well tolerated.363 Optimization of the Baeyer-Villiger (BV) oxidation of ketones by using urea⋅H2O2 complex as a convenient source of peroxide, which is activated by PhCN under mildly basic (KHCO3) reaction conditions in trifluoroethanol, forms the active peroxy imidic acid in situ which is converted to the ester. The protocol is applicable to a range of ketones in moderate to excellent yields (30–91%) with excellent and predictable regioselectivity and migration proceeding with the retention of configuration and good to excellent regioselectivities (7:1 to 20:1).364 DFT calculations for the oxidation of benzyl alcohol to acetaldehyde by a Cu(II)/L TEMPO catalyst system in alkaline aqueous solution (L = bis[2-N-(4-fluorophenyl)- pyrrolyl carbaldimide] indicate that the catalytic cycle consists of catalyst activation, substrate oxidation, and catalyst regeneration. Four pathways for the catalyst activation step are considered. The rate-determining steps in these pathways are proton transfers, in which water participation plays a major role. In consideration of the high concentration of the solvent water, paths 3 and 4 are supposed to be competitive during the reaction, 365 path 4 being more favourable. Oxidation of diethyl ether to acetaldehyde by NO2 has been studied by DFT at the B3LYP/6-31+G(d,p) level and found to proceed in four steps. (i) The diethyl ether reacts with NO2 to produce HNO2 and diethyl ether radical, (ii) the radical then directly combines with NO2 to form CH3CH(ONO)OCH2CH3, (iii) 3 Oxidation and Reduction 189

CH3CH(ONO)OCH2CH3 is further decomposed into CH3CH2ONO and CH3CHO, and, finally, (iv)3 CH CH2ONO continues to react with radical NO2 to yield simultaneously CH3CHO, HNO2, and NO. Based on the calculations, the third step is the rate-limiting step with the higher energy barrier of 32.87 kcal mol−1. The calculated oxidation mechanism agrees well with Nishiguchi and Okamoto’s experiments and the proposal that 366 high temperature may be required for the oxidation of ethers by NO2. 2− The kinetics of oxidation of malachite green by dithionite ions (S2O4 ) in aqueous solution has been studied. The stoichiometry of the reaction is 1:1, and the rate increases with increase in ionic strength and dielectric constant of reaction medium. The observed Michaelis–Menten kinetics and catalysis by the added ions suggest that the reaction proceeds through the outer-sphere pathway.367 The mechanism of glycine oxidation by pyrroloquinoline quinone (PQQ) in aqueous solution has been subjected to quantum chemical calculations, in light of a new crystal structure of PQQ under alkaline conditions. The first mechanism investigated by this calculation is a ‘step-wise’ mechanism, that is, a nucleophilic attack on C(5) or C(4) by the nitrogen atom of glycine, and proton and electron transfer to PQQ. The second mechanism features a simultaneous ‘concerted’ process that does not involve the nucleophilic attack but includes proton and electron transfer to PQQ.368 Oxidation of aryl alkyl alcohols and long-chain alcohols by O2, catalysed by N-heterocyclic carbenes and thus avoiding metal catalysts, has been achieved under mild conditions. Aryl methyl alcohols containing electron-donating groups or EWGs are oxidized to the corresponding carboxylic acids in moderate to high yields, but the latter give higher yields than the former. The work-up is straightforward, with no need for column chromatography.369

Reductions

A reducing system comprising InI3-1,1,3,3-tetramethyldisiloxane (TMDS) in CHCl3 selectively reduces a variety of secondary aromatic/aliphatic amides to the corresponding secondary amines. The system tolerates a variety of functional groups, including an alkyl, a cyano, halogens, a sulfide unit, a heterocyclic ring, an ether chain, and aterminal alkene. The protocol could even reduce N-alkylated secondary amide to a certain extent at higher temperatures.370 The kinetics of reduction of 3,7-bis(dimethylamino)phenazothionium chloride (MB+) by benzenethiol in aqueous solution has been determined for the range 0.3 ≤ 3 3 H+ ≤ 0.9 mol dm− and ionic strength 0.4 ≤ 𝜇𝜇 ≤ 1.0 mol dm− . The reaction is first order in both oxidant and reductant, and acid dependence displays an inverse effect with the + + −1 + rate law: −d[MB ]/dt = (Kk4[H ] + k6)([MB ][C6H5SH]). The rate increases with increase in the ionic strength of the reaction medium and also with decrease in the dielectric constant. Added HCOO− and Cl− enhanced the rate, and a test for free radical involvement was positive. A plausible mechanism consistent with these observations has been proposed.371 Reductive nucleophilic addition to N-methoxyamides, catalysed by IrCl(CO)(PPh3)2, takes place in presence of (Me2HSi)2O in high yield with high chemoselectivity in the presence of a variety of sensitive functional groups such as esters and nitro groups. Mechanistically, the reduction step does not form an enamine, but an N,O-acetal, in contrast to the case with t-amides. Treatment of the resulting 190 Organic Reaction Mechanisms 2015

N,O-acetal intermediate with an organometallic reagent and an acid provides a 372 substituted N-methoxyamine without racemization at the 𝛼𝛼-position. Free energies of activation have been determined by the kinetic study of the FLP-catalysed hydrogenation and deuteration of N-benzylidene-t-butylamine by using three Lewis acids, namely B(C6F5)3, B(2,4,6-F3–C6H2)3, and B(2,6-F2–C6H3)3, which couple with substrate nitrogen. Reactions catalysed by the weaker Lewis acids, partially fluorinated, display autoinduced catalysis arising from higher free activation energy (2 kcal mol−1) for the H2 activation by the imine compared to the amine; the imine reduction with D2 proceeds with higher rates. This effect results from a primary inverse equilibrium isotope effect in the deuterohydrogenation of the imine, caused by the higher exothermicity of the D2- activation product, thus counterbalancing the primary and secondary isotope effects.373 A high E-selectivity in the alkyne reduction to alkene by H2 is reported at elevated temperatures in the presence of the optimal catalyst (NHC)Ag–RuCp(CO)2 (NHC = N-heterocyclic carbine). The transformation is tolerant of many reducible functional groups. Computational study of H2 activation thermodynamics guided rational catalyst development. The mechanisms of bimetallic alkyne hydrogenation and alkene isomerization are proposed.374 Ferrocenyl phosphine thioether ligands, having no deprotonat- able functions, support iridium-catalysed ketone hydrogenation in combination with a strong base co-catalyst. Computational investigations, which include solvent effects, demonstrate the thermodynamically accessible generation of the tetrahydrido complex − [IrH4(PS)] and suggest an operating cycle via a [Na+(MeOH)3⋅⋅⋅Ir–H4(PS)] contact ion pair. The cycle involves an outer-sphere stepwise H−/H+ transfer, and the proton originates from H2 after coordination and heterolytic activation. The base plays the dual role of generating the anionic complex and providing the Lewis acid co-catalyst for ketone activation.375 de A highly efficient method for the enantioselective hydrogenation of 𝛼𝛼,𝛽𝛽-unsaturated nitriles to optically active saturated nitriles in CH2Cl2 using the (R,R)-f-spiro Phos complex (105) as the catalyst in the presence of [Rh(COD)Cl]2 is achieved with complete conversion and high enantioselectivity (96%) under mild conditions. Similar results are obtained on replacing CH2Cl2 by DME and dioxane solvents. A wide range of 𝛼𝛼,𝛽𝛽-unsaturated nitriles including the (E)- and (Z)-isomers of 3-alkyl-3-aryl, 3,3-diaryl, and 3,3-dialkyl 𝛼𝛼,𝛽𝛽-unsaturated nitriles were hydrogenated to the corresponding chiral nitriles with up to 99.9% ee and TONs up to 10,000.376 ee

(105) 3 Oxidation and Reduction 191

The asymmetric 𝛽𝛽-hydrogen transfer reduction of 𝛼𝛼-trifluoromethyl ketones in toluene is effected using diethylzinc as the 𝛽𝛽-hydrogen donor in the presence of 1,2-diamino phosphinamide chiral ligand (106) as the catalyst. The corresponding alcohol products are obtained in up to 88% yield and 73% ee. The method is successfully applied to the chemo- and enantio-selective reduction of 𝛼𝛼-methyl/trifluoro methyl diketone, affording the fluorinated hydroxylketone product in 88% yield and 70% ee; a possible TS was 377 proposed. ee

NH O P N H

(106)

The mechanism of hydrogenation of amides to alcohols and amines, catalysed by a bipyridyl-based (PNN)Ru(CO)(H) pincer complex, is investigated using DFT computations. The results show that the reaction occurs via metal–ligand cooperation involving aromatization/dearomatization of the PNN ligand (PNN = (2-(di-t-butyl- phosphinomethyl)-6-(diethylaminomethyl) pyridine). The catalytic cycle contains four steps involving the activation of two H2 molecules, formation of the amine, and formation of the alcohol. The highest free-energy barrier for the reaction (27.8 kcal mol−1) appears in the process of formation of the amine. The overall process is exergonic by 1 378 10.3 kcal mol− , which is the driving force for the catalytic reaction. ee Quantitative asymmetric hydrogenation of acetophenone (AP) in 2-propanol containing potassium t-butoxide using a combined system of (R)-Ph–BINAN–H–Py (107) and Ru(𝜋𝜋-CH2C(CH3)CH2)2(cod) (108) proceeds with virtually no change in (107) and (108), giving (R-PE) and (S-PE) (PE = 1-phenylethanol) with an R/S ratio of 97:3. The detailed reaction sequence in the preliminary process is unclear. Most probably, an infinitesimal amount of reactive and unstable2 RuH L(109) is very slowly and irreversibly generated from (108) by the action of H2 and (107), which rapidly catalyses the hydrogenation of AP via Noyori’s donor–acceptor bifunctional mechanism. A CH-𝜋𝜋-stabilized Si-face selective TS, CSi, gives (R)-PE together with an intermediary Ru amide (110), which is inhibited predominantly by formation of the Ru enolate of AP. Rate-determining hydrogenolysis of (110) completes the cycle. This mechanism is fully supported by a series of experiments including a detailed kinetic study, rate law analysis, simulation of t/[PE] curves with fitting to the experimental observations atthe initial reaction stage, X-ray crystallographic analyses of (109)-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities.379 192 Organic Reaction Mechanisms 2015

NH N N NH

(107)

H N δ− N H N N δ+ N δ+ N Me Ru δ− H Ru H H H Ru N N B Me

(108) (109) (110)

l-Valine-derived N-sulfinamide (111) is an efficient catalyst for the asymmetric reduction of N-aryl and N-alkyl ketimines with trichlorosilane in toluene, affording products in up to 99% yield with 96% ee in the reduction of N-alkyl ketimines and up to 98% 380 yield with 98% ee in the reduction of N-aryl ketimines. ee F

Me HN F

Me O N O Me S Me Me Me

(111)

An enantioselective transfer hydrogenation study of various aryl-substituted 1,4-benzoxazines and quinolones is reported using Hantzsch ester as the stoichiometric hydride source in the presence of 9-anthracenyl-substituted SPINOL- derived phosphoric acid catalyst (112) in dichloromethane. The corresponding optically active dihydro-2H-1,4-benzothiazines and tetrahydroquinolines are obtained in high 3 Oxidation and Reduction 193 yields (85–99%) with excellent enantioselectivities (91–99%) under mild reaction conditions.381 ee

O O

P HO O (112)

Transfer hydrogenations of electron-deficient unsaturated compounds, such as Michael acceptors, imines, a carbodiimide, and an azo compound, promoted by NHCs and water is reported. It is interesting to note that NHCs act as reducing reagents, being converted into the NHC oxides. The proposed reaction mechanism is consistent with the results of deuterium-labelling experiments.382

Other Reactions Reactions such as halogenations, hydrohalogenations, halohydrin formations, hydra- tions, epoxidations, other oxidations, carbene additions, and ozonolyses are investigated to elucidate the correlation between alkene reactivities and their enthalpies of hydrogenation (ΔHhyd). For the addition of electrophiles to unconjugated hydrocarbon alkenes, ln(k) is a linear function of ΔHhyd (r = 0.98 or greater). None of the several previously proposed correlations of ln(k) with the properties of alkenes or with linear free-energy relationships matches the generality and accuracy of the simple linear relationship found herein. Exceptions occur only when the addition of an electrophile, usually H+, can form a relatively stable carbocation (tertiary, benzylic, or allylic) and only in solvents with high dielectric constants, which solvate the carbocation, as in acid-catalysed hydra- tions in water. 13C NMR chemical shifts can also be used to predict, or rationalize, the regioselectivity of all such additions.383 Reaction of the calcium hydride complex (DIPPnacnac-CaH⋅THF)2 (DIPPnacnac = [(2,6-i-Pr2C6H3)NC(Me)]2CH) with pyridine is much faster and more selective than that of the corresponding magnesium hydride complexes. The hydride anion is exclusively transferred to the 2-position of pyridine, and at higher temperatures no 1,2 → 1,4 isomerization is observed. The product DIPPnacnac-Ca(1,2-dihydropyridide)⋅(pyridine) shows fast ligand exchange into homoleptic calcium complexes and therefore could not be isolated. The higher reactivity of calcium hydride complexes is exemplified by the reaction with 2,6-lutidine, a pyridine with blocked 2- and 6-positions, whereas magnesium hydride complexes showed no reaction; the more reactive calcium hydride complex gave slow conversion to a 1,4-DHP product. The striking selectivity difference in 194 Organic Reaction Mechanisms 2015 the dearomatization of pyridines by Mg or Ca complexes can be rationalized by DFT calculations.384 In an attempt to have an efficient oxidative amidation method for the transformations of 𝛼𝛼-carbonylimines into 𝛼𝛼-carbonylamides, the combinations of TBHP⋅pyridine, TBHP–CuBr, MgSO4–TBHP-pyridine, and SeO2⋅pyridine are explored. SeO2⋅pyridine emerged as a versatile reagent in the study to promote 𝛼𝛼-carbonylimine formation with weak nucleophilic amines as reflected by the yield of the product 𝛼𝛼-carbonylamides. The reactions afforded the desired products in good yields (90–95%) irrespective of the nature of the substitution on 𝛼𝛼-carbonyl imines. The reaction conditions work well with both 𝛼𝛼-carbonylimine (X) as substrate and with (X) generated in situ. Mechanistic studies show that 𝛼𝛼-carbonylimine (–CO–C=N–)-based compounds are a central feature of the reaction. It is found that an adjacent CO moiety enhances the electrophilicity of the 385 C=N system, which favours attack of the oxidant (TBHP or SeO2). The three singlet carbenes (113)–(115) are compared with respect to their hydrogenation reactions. The TS structures are similar for all three carbenes, but the barrier for (113) is more than 20 kcal mol−1, almost zero for (114), and 7 kcal mol−1 for (115). The energy barrier is prohibitively high for a reaction to occur thermally at 3 K, thus it lends strong support to the assumption that quantum mechanical tunnelling is involved in the hydrogen insertion reaction of these singlet carbenes. The first phase in the hydrogenation is the electrophilic interaction between the p orbital at the carbene centre with the s orbital of hydrogen. This phase is rate-determining, and therefore the barriers increase with decreasing electrophilicity from (114) with an early TS via (115)to(113) with a late TS.386

C Pri C N But FF Pri

(113) (114) (115)

The reaction of pyridine with an equimolar amount of HBpin in C6D6, under mild con- F F ditions, catalysed by the metal-free Ar 2BMe (Ar = 2,4,6-tris(trifluoromethyl)phenyl), is highly chemo- and regio-selective and is quantitative in nature, yielding 1,4- dihydropyridine as the only regioisomer through the formation of an intermediate F [Py2Bpin][Ar 2B(H)Me]. The key to this reaction is the formation of an FLP by the F bulky Ar 2BMe with pyridine. Experimental (NMR) and theoretical studies (DFT) of F 387 the mechanism reveal that [Py2Bpin][Ar 2B(H)Me] is formed as the intermediate. Hydrosilylation and deoxygenation of a broad range of aryl and alkyl ketones using Et3SiH in the presence of CD2Cl2, catalysed by highly electrophilic phosphonium cations, affords the corresponding alkane and silyl ethers. The dependence of the reaction outcome on Lewis acidity is investigated, and DFT methods are used to probe the deoxygenation mechanism.388 The combination of a phosphorus(V)-based Lewis acid with diaryl amines or diaryl silylamines promotes the reversible activation of H2 and is exploited in metal-free 3 Oxidation and Reduction 195 catalytic olefin hydrogenation. Thus the hydrogenated olefin in isolated yield of92%is obtained when Ph2C=CH2 is heated with a mixture of the base p-Tol2NSiEt3 (formed by mixing Et3SiH and p-Tol2NH) and the catalyst ([FP(C6F5)3][B(C6F5)4]) under H2. Experimental and DFT studies suggest an FLP-type activation mechanism.389 Quantum chemical calculations are used to investigate the different mechanistic pathways of the iodine(III)-mediated 𝛼𝛼-tosyloxylation of ketones. The calculations suggest an unprecedented iodine(III)-promoted enolization process and that the stereochemistry- ′ determining step would be a SN2 -type reductive elimination process. There are indica- tions that iodonium intermediates could serve as proficient Lewis acids to enhance the electrophilicity of carbonyl compounds and other electrophiles in general.390 The formation of new types of alkylation products from redox and/or reductive ami- nations is observed in the Bi(NO3)3⋅5H2O-catalysed reaction of indoline with a variety of benzylic ketones. The study provides important mechanistic insights into the effect of the electronic nature of the ketones on the course of the reaction. The formation of an iminium ion from a ketone group and indoline is the key step in these reactions. The iminium ion is transformed to N-alkyl indoles by isomerization during the redox amination reaction. The inherent reducing power of indoline allows an intermolecular hydride transfer to this iminium ion and opens up a new path for N-alkyl indolines via a reductive amination protocol.391 A series of 21 complexes (116) (M = Ru(II), Os(II), Ir(III); arene = p-cymene, − 1 2 3 4 5 6 C5Me5 , and R being H (L ), Me (L ), OMe (L ), CN (L ), CF3 (L ), Br (L ), or NO2 (L7)) are tested as (pre)catalysts for the transfer hydrogenation of carbonyl groups. A remarkable reactivity is shown by these complexes even at very low catalyst loadings (TONs up to 10,000). The electronic effects of the ligands as well as different substrates were investigated to provide mechanistic elucidation.392

arene + M Cl N R N N N Me (116)

Oxime formation from 4-pyridine carboxaldehyde N-oxide occurs with rate- determining carbinolamine dehydration under acidic and neutral conditions. The saturation effects at pH ∼ 7 are indicative of the carbinolamine accumulation, and the occurence of exclusive general acid catalysis in the pH range investigated suggests that the carbinolamine dehydration is rate-determining, and not amine attack. No evidence is found for the usual pH-independent reaction typical of the addition of weakly basic amines to the carbonyl function. The break observed in the pH–rate plot at pH near 0.5 is interpreted in terms of protolytic equilibrium of the substrate.393 2+ 2+ The reaction of phosphenium dication [(Ph3P)2C–P–Ni-Pr2] , X , towards pyridine 2+ N-oxide (O-py) affords oxophosphonium dication [(Ph3P)2C(Ni-Pr2)P(O)(O-py)] , Y2+, which is stabilized by a less nucleophilic O-py ligand instead of pyridine (py). 196 Organic Reaction Mechanisms 2015

This compound is identified as an analogue of the elusive Criegee intermediate because it undergoes oxygen insertion into the P–C bond. According to computational analysis, the mechanism for the oxygen insertion resembles Baeyer–Villiger (BV) oxidations.394 The epoxy monomers (S,S)- or (S,R)-3-(glycidyloxy)methyl-2,2′-bis(methoxymethyl- oxy)-1,1′-binaphthalene and (S,S)- or (S,R)-6-(glycidyloxy)methyl-2,2′-bis(methoxy- methyloxy)-1,1′-binaphthalene, derived from chiral BINOL and epichlorohydrin, undergo anionic polymerization and deprotection of the MOM groups to give soluble polyethers, which are used as catalysts to induce the enantioselective borane reduction of prochiral ketones (with up to 98% yield and over 99% ee). The recovered polyethers could be reused over six cycles without losing their enantioselective induction ability.395 ee Good to excellent yields of 𝛾𝛾-lactones are obtained fom a range of 𝛿𝛿-sultones when treated with t-BuOOH in the presence of t-BuOK. The protocol provides a method for ‘remote carboxylation’ of alcohols at C(3), leading to 𝛾𝛾-lactones. An intermediate in the synthesis of (−)-eburnamonin is prepared using this approach.396 DFT in conjunction with various exchange-correlation functionals is used to investigate the mechanisms of OH radical-initiated oxidation of thiophene under argon. The results are compared with the benchmark CBS-QB3 theoretical results. Variational TS theory and the statistical Rice–Ramsperger–Kassel–Marcus theory are used to estimate the kinetic rate constants. Consistent with experimental results, the computed branching ratios indicate that the most kinetically efficient process involves OH addition toa carbon atom adjacent to the sulfur atom. Nucleus-independent chemical shift indexes and NBO analysis show that the computed activation energies are dictated by changes in aromaticity and charge-transfer effects due to the delocalization of lone pairs from 397 sulfur to empty 𝜋𝜋* orbitals. A protocol involving InBr3-promoted direct acylation of terminal alkynes using aldehydes in Et3N and Et2O is developed to access the corresponding alkynyl ketones (ynones) in yields up to 83%. The oxidative coupling proceeds exclusively to afford alkynyl ketones and not propargylic alcohols as had been reported in the previous addition reactions of alkynes to aldehydes. Observation of the alcohol, originating from the aldehyde, and an isotope labelling study suggest that this transformation proceeds through the addition of an organoindium(III) to an aldehyde followed by an Oppenauer oxidation with the next aldehyde. Basically, excess of aldehyde plays the dual roles of substrate and hydride acceptor.398 9,14-d2-7-Dehydrocholesterol is synthesized to investigate the KIE in the 𝛼𝛼-tocopherol-mediated peroxidation (TMP) of 7-dehydrocholesterol. Subsequently, the co-oxidation of 9,14-h2-25,26,26,26,27,27,27-d7- and 9,14-d2-7-DHC is carried out in the presence of 𝛼𝛼-tocopherol under conditions favourable to TMP. The KIE obtained for the H(9) transfer, 21 ± 1, is significantly larger than classical KIE values reported for hydrogen atom transfer in peroxidation. This large KIE value suggests that tunnelling is important in the H-transfer to a tocopheryl radical in the TMP of 7-dehydrocholesterol.399 The aluminum hydride [LAlH(OTf)] (L = HC(CMeNAr)2, Ar = 2,6-i-Pr2C6H3) is an excellent catalyst both in the hydroboration and the addition of trimethylsilyl cyanide 3 Oxidation and Reduction 197

(TMSCN) to aldehydes and ketones. The compound is synthesized by the reaction of [LAlH2] with MeOTf (Tf = SO2CF3), and has a strong Lewis acidic character since the triflate substituent increases the positive charge at the aluminium centre. Quantum mechanical calculations suggest that the catalyst initially acts as a hydride donor to the carbonyl group.400 The setup of simultaneous operando EPR/UV–vis/ATR-IR spectroscopy for mechanistic studies of gas–liquid phase reactions has been applied to the well-known copper/TEMPO-catalysed oxidation of benzyl alcohol. The study suggests that there is no direct redox reaction between TEMPO and Cu(I) /Cu(III). The role of TEMPO is to II ⋅− stabilize the (bpy)(NMI)Cu -O2 -TEMPO intermediate formed by electron transfer 401 from Cu(I) to molecular O2; NMI = N-methylimidazole. The pyridylidene intermediate, generated from a pyridinium salt and a base, traps H2 and forms dihydropyridine, which acts as reducing agent towards organic electrophiles. A catalytic process is established by coupling the hydrogen-activation step with subsequent hydride transfer from the dihydropyridine to an imine. Treatment of the N-phenylimine of phenyl trifluoromethyl ketone with N-mesityl-3,5-bis(2,6- dimethylphenyl)pyridinium triflate and LiN(SiMe3)2 under H2 results in high conversion into the corresponding amine. The proposed catalytic cycle for pyridylidene-mediated 402 H2 activation coupled with catalytic imine reduction is illustrated in Scheme 11. A novel zinc-catalysed dehydrogenative C(sp2)–H/C(sp)–H cross-coupling of terminal alkynes with aldehydes provides a simple way to access ynones in yields up to 88% from readily available materials under mild reaction conditions. Good reaction selectivity and efficiency is achieved with a 1:1 ratio of terminal alkyne and 403aldehyde. Various thiourea compounds have been tested for catalytic activity in the synthesis of a broad range of -CF amine precursors having a tertiary C stereocentre, from the 𝛽𝛽 3 𝛽𝛽 reaction of 𝛽𝛽-CF3 nitroalkenes with Hantzsch esters (117) in the presence of toluene as the solvent. Thiourea (118) is the best catalyst, and the solvent 𝛼𝛼,𝛼𝛼,𝛼𝛼-trifluorotoluene provides slightly better results than toluene at much lower temperatures (−20 ∘C).404 The existence of P-hydroxytetraorganophosphorane, the long-postulated intermediate in phosphonium salt and ylide hydrolysis, is established by spectroscopic observation and characterization by low-temperature NMR. The results require modification of the previously accepted mechanism for ylide hydrolysis: p-hydroxytetraorganophosphorane is generated directly by 4-centre reaction of ylide with water. Finally, there is evidence that the first step of ylide hydrolysis is not protonation of the ylide, but rather isthecon- certed addition of an O–H bond across the P=C bond.405 Asymmetric synthesis of some derivatives of the homoisoflavone class,S ( )-(−)- and (R)-(+)-5,7-O-dimethyleucomols, and (−)-homoisoflavone epoxide, based on the asymmetric oxidation of the corresponding enol phosphates (derivatives of racemic 3,9-dihydroeucomin dimethyl ether), is described. The influence of electronic and steric effects of the enol phosphate 406 substituents on the facial stereoselectivity of oxidation is observed. ee A computational study at the M06-2X/6-311+G(d,p) level is made to test the hypoth- esis that in the presence of an excess of o-benzyne, different cycloalkanes could be totally desaturated through consecutive double hydrogen atom transfers. Systems able to undergo such reactions are suggested.407 198 Organic Reaction Mechanisms 2015

i TfO− Pr But Pri But N+ Pri But Pri

HN(SiMe3)2 LiN(SiMe3)2

Pri H But 2 Pri But N+ + LiTfO Pri But H i Pr Pri N

F But Pri H LiTfO N F F But H H Pri t TfO− Pri Bu i t i Pr Bu Pr Li+

+ N + − But N Pri F H t Bu H F F N Pri F

F F

Scheme 11 3 Oxidation and Reduction 199

Me Me Me O O O Me H H Me O C C O Me N N N Ar Me S Me N Me Me Me H Me

(117) (118)

The redox-neutral C–H annulation of pyrrolidine and 1,2,3,4-tetrahydroisoquinoline with 𝛼𝛼,𝛽𝛽-unsaturated aldehydes and ketones, providing access to alkaloid-like structures, is reported. Carboxylic (benzoic) acid-promoted generation of a conjugated azo- methine ylide is followed by 6𝜋𝜋-electrocylization, and, in some cases, tautomerization. The resulting ring-fused pyrrolines are readily oxidized to the corresponding pyrroles or reduced to pyrrolidines.408 The interaction paths of l-ascorbic acid (AAH2), hydroxyl radicals, and water clusters are studied with DFT calculations. The regioselectivity of OH⋅ addition is also examined by using Frontier-orbital analyses. The TSs for electrolytic dissociation of AAH2 and intermediate carboxylic acids have very small activation energies through proton transfers along hydrogen bonds. The ionized species (anions) are subject to elec- ⋅ ⋅− trophilic attack of OH . The elementary processes of AAH2 → A → dehydroascorbic acid → diketogulonic acid → threonic, oxalic, xylonic, and lyxonic acids are investigated and discussed. Those involved in the conversion of dehydroascorbic acid into a bicyclic hemiketal are also examined as a side-chain participating reaction. The oxidation and degradation of vitamin C up to threonic acid are described mainly as a ⋅ 409 donor (AAH2)–acceptor (OH ) reaction. The organo-catalyst compounds (119) and (120), consisting of carbon, hydrogen, and nitrogen only, not only bind CO2 reversibly via the formal insertion of CO2 into a C–H bond of the C5 ring but also catalyse the hydroboration of CO2 with 9-borabicyclo[3.3.1]nonane to methylborylethers, which upon hydrolysis produce methanol. These organocatalysts feature carbon-centred reversible CO2 binding, broad borane scopes, and high catalytic activities.410

H H − −

Me N + N N+ Me

Me (119) (120)

N-Substituted 𝛽𝛽,𝛾𝛾-dihydroxy-𝛾𝛾-lactams, synthesized from 1-malic acid using reductive cyclization, are convenient substrates for Petasis-like reactions with boronic acids 200 Organic Reaction Mechanisms 2015 promoted by boron trifluoride–diethyl ether. Under optimized conditions in 1,1,1,3,3,3- hexafluoro-2-propanol, both electron-rich and electron-deficient boronic acids areused for the nucleophilic additions to cyclic N-acyliminium ions derived from 𝛽𝛽,𝛾𝛾-dihydroxy- 𝛾𝛾-lactams. cis-Diastereoselectivity is observed in the Petasis-like reactions when using electron-deficient boronic acids, while electron-rich boronic acids resulted in noorpoor selectivity, This is explained by chelation-controlled addition and direct addition of boronic acids to N-acyliminium ions, respectively.411 Literature findings on facial selectivity of the Sharpless asymmetric dihydroxylation (SAD) of isobutyl angelate are contradictory and partly in conflict with the Sharpless mnemonic. A systematic screening of the SAD of esters and amides of angelic, tiglic, and methacrylic acid is carried out. Enantiocontrol took place in 14 of the 15 reactions, culminating at 99% ee for the Weinreb amide of tiglic acid. The claim that isobutyl tiglate is dihydroxylated with the opposite facial selectivity because of a preference for a ‘Chapleur transition state’ is shown to be false. The absolute configurations of all the non-racemic products are established by (stereo) chemical correlations. The finding is that they conform to the Sharpless mnemonic without exception. The graphical representation is given in 121.412 ee Me O + AD-mix β OBui found on reinvestigating Me asymmetric reported in dihydoxylations the literature of unsaturated acid calculated in derivatives the literature

Me O Me O Me O

HO OBui HO OBui HO OBui HO Me HO Me HO Me R,R (60% ee) S,S (48% ee) R,R (82% ee) (121)

The Lewis acidity of the synthesized bis(perfluorocatecholato)silane (Si(catF)2) is investigated. Its ability to bind several common classes of Lewis bases is demonstrated by the coordination of fluoride, triethylphosphine oxide, and N,N-diisopropylbenzamide. A bis(perfluorocatecholato)fluoro silicate complex is immediately formed on adding tris(dimethylamino)sulfonium difluorotrimethyl silicate to Si(catF)2 in tetrahydrofuran. Additionally, it catalyses the hydrosilylation and silylcyanation of electron-deficient aldehydes under mild conditions. A stereogenic silicon substrate is employed, in combination with solvent- and salt-effect studies, to provide evidence for a carbonyl activation 413 mechanism involving an ionic intermediate. ee A mild and efficient catalysis by SPINOL-derived phosphoric acidR ( )-STRIP (122) in the reaction of hydrazine with ketone, giving 1,4-diketone with a 72% yield and enantioselectivity of 96:4, is achieved using the weakly acidic resin Amberlite CG50 3 Oxidation and Reduction 201

and benzoic acid in presence of xylene and 10 equiv of H2O. A higher or lower amount of water leads to a decrease in enantioselectivity or yield, respectively.414

Pri Pri

Pri O O P O OH Pri

Pri Pri (122)

DFT calculations are made to test metal-free catalytic systems, based on the FLP concept, that are cheaper and greener alternatives for the conversion of alcohols to the corresponding ketones. Careful investigations reveal that new FLPs can be designed with a weaker interaction between the nitrogen and boron centres, which can be ruptured and regenerated during the alcohol dehydrogenation catalysis process. Several metal-free FLPs were identified during this investigation which would have barriers comparable to or lower than the calculated barrier for the slowest step for the state-of-the-art acceptor- 415 less alcohol dehydrogenation metal catalyst present today. ee The ligand (123) is treated with trityl tetrakis(pentafluorophenyl)-borate in bromoben- zene when the selective removal of methyl anion results in the formation of the very reactive FLP (124). Because of the high reactivity of (124), it is prepared in situ, and some of its reactions are described. The addition of a small amount of dichloromethane to the reaction mixture results in the addition product (125). The in situ generated (124) on standing undergoes a typical hydride abstraction reaction from the isopropyl 𝛼𝛼-CH + position of the amino group in (124) by the adjacent [Cp*2Zr] Lewis acid. This process generates the reactive bifunctional zirconium hydride/iminium intermediate (126). Subsequent iminium/enaminium tautomerization to (127) is followed by H2 elimination, which provides a pale yellow solid compound (128) that is apparently formed from (124) by the loss of dihydrogen. The work-up of the reaction mixture consisting of in situ prepared (124) and added phenylacetylene gives the product (129) as a white solid in 76% yield. Compound (124) cleaves H2 heterogentically, giving (130), which reduces + − benzaldehyde to give the respective [Zr]OCH2Ph (131) and is able to transfer the H /H pair to styrene to give ethylbenzene.416 The regioselective reductive transposition of primary allylic bromides, catalysed by a t biphilic organophosphorus (phosphetane) catalyst (132) in toluene with LiAlH(OBu 3), results in a combined yield of 96% as a 94:6 ratio in favour of the 𝛾𝛾-reduction product 5 and supports the formation of a penta-coordinate (𝜎𝜎 -P) hydridophosphorane as a key reactive intermediate. The experimental and computational studies are consistent with a 202 Organic Reaction Mechanisms 2015

i NPr 2 O O * + O O CP 2Zr + i [Ph C+][B−] NPr 2 * 3 H2 * C6H5CHO O CP 2Zr CP* Zr+ i CP 2Zr +NPri 2 NPr 2 2 H − − Me [B ] [B ] H H − [B ] (131) (124)(130) (123) R C C 2 H Cl 2 CH O 60 °C * CP 2Zr 3 h + i O [B−] NPr 2 * t CP 2Zr H R = (i) Ph; (ii) Bu +NPri 2 (129) R Cl Cl (125) O O * * CP 2Zr CP 2Zr +N Pri +N Pri H H Pri Me (126) (127)

−H2 O * CP 2Zr +N Pri

(128) Me 3 Oxidation and Reduction 203

5 unimolecular decomposition of the 𝜎𝜎 -P hydridophosphorane via a concerted cyclic TS that delivers the observed allylic transposition and completes a novel P(III)/P(V) redox 3 4 5 417 catalytic cycle involving the interconversion of discrete 𝜎𝜎 -P, 𝜎𝜎 -P, and 𝜎𝜎 -P species.

Me P Me

(132) Me

The Diels–Alder reactions of cyclopentadiene, cyclohexadiene, and cyclohepta- diene with a series of symmetrical and asymmetrical dienophiles are studied with quantum chemical calculations and analysed with the distortion/interaction model. Cyclopentadiene is highly reactive in Diels–Alder reactions because only minimal out-of-plane distortion is required to achieve the TS geometry compared with other cyclic and acyclic dienes. Asynchronous TSs have significant out-of-plane distortion about only one double bond. With heterodienophiles, such as nitrosobenzene and N-phenyl-1,2,4-triazolin-3,5-dione, the asynchronicity of the TSs results in similar reactivities for all three cyclic dienes.418 A mild method for the regiospecific acylation reaction between electron-deficient N- heterocycles (isoquinoline, quinolones, and quinoxalines) and a series of alkylbenzenes possessing both electron-donating as well as electron-withdrawing substituents is studied under N2 using AlCl3 (Lewis acid) as the catalyst and TBHP in decane as the oxidant, to give the corresponding acylation products in moderate to good yields. This protocol is an alternative to the classical Minisci reaction.419 The difference in reactivity in the autoxidation of tetrahydropyran (THP) and tetrahydrofuran (THF) is investigated using ab initio and DFT calculations at the BH and HLYP/aug-cc-pVDZ//BHandHLYP/cc-pVDZ level. The energy barrier for H-abstraction from THP is 104.1 kJ mol−1, whereas that calculated for THF is 94.1 kJ mol−1. The barriers are lowered to 98.0 (THP) and 84.4 kJ mol−1 (THF) if solvation effects are included in the calculations. The potential energy surface for the −1 coupling of THP radical with O2 is 11.2 kJ mol (BH and HLYP/6-311G**), whereas no barrier is found for the reaction involving THF. Analysis of the Kohn–Sham singly occupied molecular orbitals (SOMOs) in the hydroperoxy complexes reveals that the SOMO of the THP complex would be blocked by the neighbouring H atoms in the THP ring. These factors would work together to delay the autoxidation of THP.420 A highly efficient chiral Brønsted phosphoric acid133 ( )-catalysed protocol, free of metals and additives, is developed for the asymmetric transfer hydrogenations of 2-alkyl- and 2-phenyl-substituted quinoline derivatives in diethyl carbonate using ∘ Hantzsch ester as the H2 source. The protocol at −10 C provides enantiomerically pure 1,2,3,4-tetrahydroquinoline derivatives with yields up to >99% and enantioselectivity up to 99% ee. Changing the alkyl group to a phenyl ring at the 2-position gives high conversion as well as excellent enantioselectivity. The result clearly confirms that the solvent diethyl carbonate is an excellent replacement for enviornmemtally harmful organic solvents.421 204 Organic Reaction Mechanisms 2015

Pri Pri O OH Pri Pri P O O

Pri Pri

(133)

The gas-phase mechanism of cyclohexane dehydrogenation catalysed by Ni2+ dimer is investigated by DFT at the B3LYP level. The first dehydrogenation occurs readily, followed by a second and third which are exothermically weaker than the first. The first dehydrogenation proceeds via a syn elimination model and yields the products H2 and 2 + [Ni2(C6H10)] . The reaction that follows divides into two competitive channels: one- face dehydrogenation (energetically dominant) and flip dehydrogenation. For the flip process, the elimination of [2H2,D2], [H2,D2], or [H2,2D2] is significantly less favoured than the products of one-face dehydrogenation. Because of the two significant minimum- energy crossing points MECP3 and MECP4, the flip process begins and finishes inthe quartet state but proceeds in the doublet state. The second and third dehydrogenations proceed on the quartet PES until MECP2 is encountered. With regard to the dissociation + 2 + of H2, Ni2 , and C6H6 from IM19, the results indicate that neither C6H6 nor [H2Ni2] 2 can dissociate from IM19. The only feasible model is that in which H2 dissociates 2 + first and leaves [Ni2(C6H6)] as the final stable product. [H–D] scrambling elimina- + tion and a Ni2 -dissociation mechanism are also excluded. The detailed flip mechanism 422 presented here explains the observed experimental phenomena. ee Unsaturated oximes undergo catalytic asymmetric hydroboration, catalysed by Rh complexes with the ligands (134)L1or(135) L2, with tmdBH (136) B1, pinBH (137) B2, and catBH (138) B3, affording the expected hydroboration products and, in the case of B1and B2, an unexpected ortho-borylated product. These results, in combination with the studies carried out with D-labelling, suggest that H/D exchange at the ortho-position is associated with hydroboration of the 𝛽𝛽,𝛾𝛾-alkene and that orthometallation or 𝜎𝜎-bond metathesis is exceptionally facile, leading to a tandem C–H activation/hydroboration reaction.423 A kinetic model, which adequately describes the experimental data and the assumed free-radical chain mechanism of the oxidative dehydrogenation of cyclohexane with nitrous oxide, is suggested and used to calculate the kinetic parameters of the reaction.424 A non-polar mechanism is established for the reduction of t-phosphine oxides by PhSiH3 on the basis of kinetic measurements and DFT calculations. The data allow prediction and verification of the applicability of the new reduction reagents and conditions for industrially attractive processes.425 DFT calculations made for peroxide bond breaking in the decomposition of dimethyl-1,2-dioxetanone reveal the absence of a biradical intermediate, conflicting with the expectations of some authors. However, this is in line with the chemiluminescence of simple 1,2-dioxetanone and helps to 3 Oxidation and Reduction 205

Ar Ar Ar Ar Me O O Me O O Me P Me P O O O N O O Me Ar Ar Ar Ar (134)(135) Ar = 3,5-dimethylphenyl Ar = 3,5-dimethylphenyl

H H O B B O HB OO O O Me Me Me Me Me Me Me (136) (137) (138) clarify recent controversy.426 Computational examination of alternative plausible mechanistic pathways for the intramolecular hydroamination of aminoalkenes using novel phenylene-diamine aluminium amido compound is presented. On one hand, a proton- assisted concerted N–C/C–H bond-forming pathway to afford the cycloamine in a single step, or, alternatively, a stepwise 𝜎𝜎-insertive pathway that involves a relatively fast and reversible migratory olefin 1,2-insertion step linked to a less rapid and irreversible Al–C alkyl bond protonolysis, can be invoked. The present study supports the stepwise 𝜎𝜎- insertive pathway. The predicted effective barrier for turnover-limiting aminolysis com- pares favourably with reported catalytic performance data.427 A data-intensive method for deriving and then predictively applying a mechanistic model of an enantioselective organic reaction is presented. As a validating case study, an intramolecular dehydrogenative C–N coupling reaction catalysed by chiral phosphoric acid derivatives, in which catalyst–substrate association involves weak, non-covalent interaction, is selected. Catalyst and substrate substituent effects are probed by systematic physical organic trend analysis. Plausible interactions between the substrate and catalyst that govern enantioselectivity are identified and supported experimentally, indicating that such an approach can afford an efficient means of leveraging mechanistic insight so as to optimize catalyst design.428 Reaction of dimethyldioxirane with excess 1,3-cyclohexadiene and 1,3-cyclooctadiene in dried acetone yields the corresponding monoepoxides in excellent yield. The second-order rate constant k2 for the monoepox- idation of 1,3-cyclohexadiene is ∼4 times that of 1,3-cyclooctadiene. DFT calculations at the B3LYP/6-31G level are consistent with a concerted electrophilic process with a spiro-TS. The calculated TS geometry shows a slight asynchronous tilt of the dioxirane plane relative to that of the remaining alkene portion of the diene and a slight tilt back from the face of the diene. Relative k2 values are determined using the difference in the calculated electronic activation energies and are consistent with the experimental relative 429 k2 values without correction for the solvent. ee The reaction of 2-methyl-1,3-butadiene and benzaldehyde with 1,3-bis(diphenylphosphino) propane ligand is chosen as the model reaction to seek the origin of the 206 Organic Reaction Mechanisms 2015 regioselectivity by using DFT calculations. The energies of the intermediates and TSs in the stages of oxidative cyclization, 𝛽𝛽-H elimination, and C–H reductive elimination are investigated; results show that 𝛽𝛽-H elimination is the rate-determining step for the catalytic cycle. C(1)-selective oxidative cyclization is favoured over the C(4) alternative, which is kinetically disfavoured relative to all the C(1)-hydroacylation steps. It is suggested that both electronic and steric effects contribute to the C(1)-selectivity. On the electronic aspect, C(1) is more electron-rich than C(4) due to the methyl group on C(2), which makes the electrophilic attack of aldehyde carbon on C(1) more favourable. On the steric aspect, the methyl group is located farther from the ligands in the C(1) TS than in that for C(4)-selective oxidative cyclization.430 The solvent isotope effect in transfer hydrogenation of H2O or CO2 by glycerol is investigated to probe the reaction mechanism for the production of lactate from glycerol under alkaline hydrothermal conditions. A deuterium transformation study is made 1 to investigate the solvent isotope using D2O, and the results are displayed in the H and 2H NMRs.431 Computational modelling of the chiral modifier/substrate interaction has been studied for the modifiers (S)-(+)-1-aminoindane and (R)-(−)-1-aminoindane, which are different from those conventionally used in enantioselective hydrogenation reactions. The selected substrates are Me pyruvate, Et pyruvate, and 1-Et-4,4-dimethyl- pyrrolidine-2,3,5-trione. DFT calculations and a BLYP functional are used to optimize the geometry of the chiral modifier/substrate complexes, and the theoretical ee is calculated from the energy of each. The calculations are carried out considering different reaction solvents through the use of the COSMO program. It is found that this simple model allows the experimental values of both the sense of enantiodifferentiation and the enantiomeric excess to be predicted with a good approximation. It also predicts the inversion of configuration whenS ( )-(+)-1-aminoindane is used as chiral modifier in polar solvents such as acetic acid and 2-propanol.432 ee The mechanisms of hydrogen release from methylamine with or without borane, alane, diborane, dialane, and boranealane are theoretically investigated. Geometries of stationary points are optimized at the MP2/aug-cc-pVDZ level, and energy profiles are refined at the CCSD(T)/aug-cc-pVTZ level, based on the second-order Moller–Plesset (MP2) optimized geometries. H2 elimination is impossible from molecular CH3NH2 because of a high energy barrier, but the results show that it is enabled by the catalysts, although borane and alane have no real influence since2 H release cannot compete with the preferred B–N or Al–N bond cleavage once a corresponding adduct is formed. Dib- orane, dialane, and borane-alane lead to a substantial energy barrier reduction through bifunctional catalysis. The similar and distinct points among various catalysts are compared. Hydrogen-bond and six-membered ring formation are two crucial factors able to decrease the energy barriers.433 The mechanisms of gas-phase thermal decomposition of alkyl-substituted cyclohexa- dienes are studied by quantum chemical calculations with theory levels Moller–Plesset perturbation theory (MP2) and DFT (B3LYP, MPW1PW91, PBEPBE, 𝜔𝜔B97XD, CAM- B3LYP, M06, and M062X) with 6-31G(d,p), 6-31++G(d,p) basis sets. Examination of the reaction pathways for each substrate indicated a preference for a molecular mechanism through a six-membered cyclic boat-like TS structure. An alkyl group substituent 3 Oxidation and Reduction 207 causes a detrimental effect on the reaction rate, compared to the parent compound 1,4-cyclohexadiene; however, the reaction is favoured in the case of 3,6-di-Me substitution. The 3,6-dimethyl-1,4-cyclohexadiene compound has activation energy 11.2 kJ mol−1 lower than the reference compound, which overcomes the effect of the most negative entropy of activation in the series. The effects of alkyl substituents in these reactions suggest a complex combination of electronic and steric influence. These reactions are characterized as highly synchronous concerted, with small predominance of C–H bond breaking in the TS.434 A chemical kinetic model for the oxidation of formic acid (HOCHO) in flames, based on theoretical work and literature data, is developed. Ab initio calculations are used to obtain the rate coefficients for reactions of HOCHO with H,2 O,andHO . Modelling predictions are generally satisfactory when compared to the experimental results of de Wilde and van Tiggelen (1968) who measured the laminar burning velocities for HOCHO flames over a range of stoichiometries and dilution ratios. The governing reaction mechanisms are outlined, based on calculations with the kinetic model. Formic acid is consumed mainly by reaction with OH, yielding OCHO, which dissociates rapidly to CO2 + H, and HOCO, which may in turn dissociate to CO + OH or CO2 + H, or react with H, OH, or O2 to form more stable products. The branching fraction of the HOCHO + OH reaction, as well as the fate of HOCO, determines the oxidation rate of formic acid. At lower temperatures, HO2, formed from HOCO + O2, is an important chain carrier and modelling predictions become sensitive to the 435 HOCHO + HO2 reaction. The reaction of acetophenone in the presence of 𝛽𝛽-cyclodextrin (𝛽𝛽-CD) is studied using the DFT method. The lowest energy of two possible complexation models is investigated. The geometrical structure confirms that acetophenone inserts into the cavity mainly from the secondary hydroxyl side. Hydrogen bonds are researched on the basis of NBO analysis, and Mulliken charge and frontier orbitals are employed to reveal the electronic transfer. The probable catalytic mechanism of 𝛽𝛽-CD is discussed in terms of the calculated parameters.436 Evidence to resolve the apparent paradox of oxidation of benzaldehyde (benzaldehyde readily undergoes autoxidation to form benzoic acid on exposure to air at room temperature, yet it can be formed in high yield from benzyl alcohol by oxidation using a variety of procedures and catalysts) is presented. It is confirmed that the presence of low concentration of benzyl alcohol (and anumberof other alcohols) inhibits the autoxidation of benzaldehyde. The required structural features for inhibition are also reported. ESR spin-trapping experiments demonstrate that benzyl alcohol intercepts, by hydrogen atom transfer, the benzoylperoxy radicals that play a key role in benzaldehyde autoxidation. A similar inhibition effect has also been observed for the aliphatic octanal/1-octanol system.437 It is experimentally and computationally shown that the reduction rate of organic disul- fides by phosphines in water, which in the absence of force proceeds by an equilibrium formation of a thiophosphonium intermediate, measured as a function of force applied on the disulfide moiety yields a usefully accurate estimation of the height oftheinner barrier. The varying stretching force is applied to the disulfide by incorporating it into a series of increasingly strained macrocycles. This force accelerates the reduction, even 208 Organic Reaction Mechanisms 2015 though the strain-free rate-determining step is orthogonal to the pulling direction. The observed rate force correlation is consistent with the simplest model of force-dependent kinetics of a multi-barrier reaction.438

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E. Gras1 and S. Chassaing2 1Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique, Université Fédérale de Toulouse Midi-Pyrénées, Toulouse, France 2Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, CNRS-UMR7177, Université de Strasbourg, Strasbourg, France

Reviews ...... 219 Generation, Structure, and Reactivity ...... 221 Carbenes in Coordination Chemistry ...... 223 Addition–Fragmentations ...... 226 Free Carbenes or Main Group Carbenoids Reactions ...... 226 Transition-Metal-Assisted Reactions ...... 230 Insertion–Abstraction ...... 234 Free Carbenes or Carbenoids Reactions ...... 234 Transition-Metal-Assisted Reactions ...... 235 Rearrangements ...... 237 Free Carbenes or Carbenoids Reactions ...... 237 Nucleophilic Carbenes–Carbenes as Organocatalysts ...... 238 Transformations Mediated by Breslow-Type Intermediates ...... 238 Transformations Non-Mediated by Breslow-Type Intermediates ...... 242 Nitrenes ...... 244 Free Nitrenes – Generation and Reactivity ...... 244 Transition-Metal-Assisted Reactions ...... 244 Heavy-Atom Carbene Analogues ...... 244 References ...... 245

Reviews Following the well-developed chemistry of diaminocarbenes, cyclic (alkyl)(amino) carbenes have recently been described as a new class of stable carbenes featuring high 𝜎𝜎-donation and 𝜋𝜋-accepting abilities. The chemistry of these carbenes from the perspective of their preparation and characterization, their numerous applications providing scarcely observed new adducts and application in coordination chemistry and catalysis, has been reviewed.1 A review on the chemistry of alkylidene has appeared, giving a brief highlight of the electronic structure and bonding situation and detailing

2 the different methods of generation from a range of precursors. Chemo-, regio-, and de diastereo-selectivities have also been surveyed followed by applications to syntheses of complex polycyclic structures especially found in natural compounds. Involvement of carbenes in the synthesis of numerous heterocycles has also been reviewed covering the generation of heterocycles (featuring N, O, and S atoms) exhibiting different levels of ring strain (three- to seven-membered ring) by way of additions or insertions of a divalent compound.3 Carbene intramolecular insertion into C–H bond positioned 𝛼𝛼 to an oxygen in an Rh-catalysed process has been covered with an in-depth explanation of the factors governing reactivities and selectivities of these reactions and an extension to natural product syntheses based on this transformation.4 The chemistry of metal carbenoids accessed from cyclopropenes has been developed in the perspective of its application to 5 C–H insertion and cyclopropanation. This highlights in a detailed fashion the various de approaches that have given access to a range of complex structures in high stereoselective fashion. C–H functionalization by insertion of carbenes (mainly generated from tosylhydrazone precursors) has been covered as a function of final step of the catalytic cycle involved in the transformation (termination by protonation, 𝛽𝛽-H-elimination, and C–N bond formation).6 In order to assess the most appropriate naming (between carbene and carbenoid) of adducts featuring a divalent carbon connected to a gold atom, a review explored the structure of gold intermediates potentially involved in a range of transformations, concluding that gold–carbene is more appropriate although a con- tinuum from metal-stabilized singlet carbene to metal-coordinated carbocation remains widely accepted.7 More synthetically relevant, a review on cycloisomerization of enynes involving a cyclopropyl gold(I)–carbene intermediate has appeared highlighting the various reaction paths and products available through such transformations.8 The use of water in a range of metal-catalysed transformations involving an N-heterocyclic carbene (NHC) has been comprehensively reviewed.9 It covers both homogeneous and heterogeneous approaches and describes transformation involving NHC–metal complexes of palladium, ruthenium, gold, rhodium, copper, iridium, silver, platinum, and nickel as well as transformation featuring NHCs as organocatalysts. The role of NHC–ruthenium complexes in the development of Z-selective cross-metathesis has been briefly reviewed with an emphasis on the origin ofthis unprecedented selectivity through the illustration of mechanistic studies and a description of the most significant synthetic applications.10 Detailed understanding of organocatalytic reaction mechanisms has been reviewed, with a specific mention of the umpolung effect induced by NHCs through the formation of Breslow intermediates.11 A more comprehensive review of organocatalysis performed by NHCs has appeared.12 Following a description of the synthesis and properties of NHCs, their various involve- ments in organocatalysis are thoroughly described from Breslow-type chemistry to Lewis base catalysis through the acylazolium-type chemistry. This illustrates the fruitful developments achieved in this field over the past 10 years. A systematic review of nitrenoids and their involvement in electrophilic amination has appeared, giving detailed insights into their preparation from a range of precursors, their structural features, and mechanistic studies accounting for their reactivities toward a range of main group organometallics.13 4 Carbenes and Nitrenes 221

Generation, Structure, and Reactivity Carbenes, especially NHCs, have proved to be excellent ‘ligands’ of main group atoms, including carbon, and allowed the generation of carbodicarbenes, these structures being mesomeric resonance structures of cumulenes. This has been exemplified by the double deprotonation of (1) that proved to allow the generation and characterization of (2) (Scheme 1). Compound (2) could also be obtained in the coordination sphere of palladium providing a competent catalyst for Mizoroki–Heck and Suzuki–Miyaura reactions.14

N N N N NaHMDS C N N N benzene N

N N N N + + 2I − (1) (2)

N N

N C N

N N

Scheme 1

Similar strategy has been applied for the isolation of an NHC-stabilized dicarbon.15 Yet under strongly basic conditions (3) only underwent reduction providing (4)ina very efficient manner. The high delocalization of the charges3 on( ) is suggestive of a low HOMO/LUMO gap standing for this easy reduction under basic conditions. This statement has been confirmed by computations. The generation of chiral unsymmetrical unsaturated carbene precursors (5) through an elegant multicomponent approach has been reported, allowing efficient applications to 1,4- and 1,6-asymmetric conjugate additions of alkyl zinc catalysed by the corresponding copper–NHC complexes.16 NHC–SiCl4 has been described as an efficient carbene transfer reagent to main group element-based Lewis acids providing a straightforward access to main group elements such as other silicon adducts and boron or phosphorous complexes when chloride abstraction by the Lewis acid is prevented.17 222 Organic Reaction Mechanisms 2015

N N + N N N N + N N 2X − (3)(4)

+ R N N

− PF6 CX2 HO R = Bui, Pri, But

X2 = H2, O (5)

Out of 11 new formamidinium precursors, 5 new acyclic diaminocarbenes (6) have been isolated and characterized spectroscopically and by X-ray diffraction of their corresponding rhodium complexes.18 The transient nature of the carbene obtained from the six other precursors could be assessed by selenium trapping experiments leading to (7). Density functional theory (DFT) computations have been carried out on boat- shaped cyclonona-3,5,7-trienylidenes (8) to predict their electronic structure and potential reactivity.19 Investigations of isodesmic reaction supported a significant stabilization by any substituent 𝛼𝛼 or 𝛼𝛼′ of the carbene centre in both singlet and triplet states. Theoretical approaches have also been carried out to assess the stabilizing effect of 20 𝛼𝛼-substitution of carbenes by ylide on a range of cyclic carbenes such as (9) and (10).

Se i i Pr 2N Pr 2N NRR′ NRR′ i i Pr 2N Pr 2N (6)(7)(8)

PMe3

N Pri N Pri

(9) (10) 4 Carbenes and Nitrenes 223

All the molecules investigated were found to exhibit a stable singlet ground state, and 𝛼𝛼-substitution by an ylide moiety was found to significantly enhance the 𝜎𝜎-donating character of the carbene. Stable carbene–borane complexes (12) were obtained from N-phosphine oxide- 21 substituted imidazolylidenes (11) via addition to B(C6F5)3. Interestingly, under heating these complexes revealed a frustrated Lewis pair (FLP) ability allowing a ∘ quantitative H2 activation from 60 C. This peculiar property is attributed to the thermal induced rotation around the N–P bond of (12) that induces the steric bulk required to achieve the FLP activity. The synthesis of B,B-disubstituted N,N-dimethylimidazol-2-ylidene boranes (13) and (14) has been achieved by Rh-catalysed insertion of diazoester into the B–H bond of substituted NHC–boranes.22 The energies of rotation around the carbenic C–B bonds have been determined by dynamic NMR spectroscopy and were found to range from 56 to 86 kJ mol−1.

Pri Pri But O N But N P P t Bu Pri O But B Pri C6F5 C6F5 C6F5 (11)(12)

+ + N N BH BH − − N SHet N CH2R Het = Benzothiazolyl, N-Phenyltetrazolyl (13)(14)

Carbenes in Coordination Chemistry A frontier orbital analysis of the various metal carbene catalysts for alkene metathesis has been carried out computationally and efficiently matched the trends experimentally observed, affording a useful predicting tool.23 A mechanistic study of the alkyne trans- hydrogenation by Cp*RuCl(cod) has highlighted the transient formation of a ruthenium carbene complex arising from gem-dihydrogenation.24 These carbene complexes have been identified through extensive NMR studies including para-hydrogen-induced polarization. These allowed identification of stabilizing features such as a proximal ORgroup and resulted in the full characterization of (15) by spectroscopic methods and X-ray diffraction. Such carbenes account for the formation of by-products such as alkene isomerization and over-reduction. 224 Organic Reaction Mechanisms 2015

Silicon-tethered dinuclear carbene–copper complexes (16) have been obtained by addition of NHC (17) to Ph2SiCl2, showing an unexpected skeleton rearrangement, followed by a double deprotonation to preform the dicarbene (18) that was finally complexed with CuCl.25 The whole reaction path has been thoroughly established through a full characterization of every compounds by multi-nuclear NMR spectroscopy and X-ray diffraction.

ClCu CuCl NPri PriN Pri NPri PriN Ru OMe N Cl i i Pr N NPri Pr N NPri HO Si Si N Ph Ph Pri Ph Ph (15) (16) (17) (18)

Cyclic (amino)(aryl)carbene (CAArC) complexes of rhodium and gold (19) have been synthesized and characterized.26 CAArC were shown to be transient intermediate as they could be trapped by elemental chalcogens providing the corresponding thio- and seleno-amides (20). They were shown to be strong 𝜎𝜎-donor and 𝜋𝜋-acceptor ligands, and their complexes are able to catalyse efficiently 3 + 2-cycloaddition, C–H activation, and aniline annulation with terminal acetylene. The addition of pyrene to palladium and nickel complexes of NHC decorated with fused polyarenes, including a pyrene unit as in (21), has been studied by UV–vis and 27 NMR spectroscopies as well as by electrochemistry. The 𝜋𝜋–𝜋𝜋 interaction between the pyrene-substituted NHC and pyrene induced a modification of the electronic properties of the metal, but was either reducing the catalyst activity in 𝛼𝛼-arylation of ketones or had no effect in Suzuki–Miyaura reactions (probably associated with the formation of nanoparticles).

Ph Ph Ph Ph Cl Bu Cl N R N R N N Pd N X Cl [M] Bu X = S, Se

(19)(20) (21)

Rhodium complexes (22) featuring a NHC-stabilized carbon(0) ligand have been used in hydroarylation of 1,3-butadienes by indole and pyrroles in a regioselective fashion.28 Reaction was shown to be triggered by the addition of a Lewis acid, LiBF4 being the most efficient one. Cross-hydroalkenylation of vinyl arenes with terminal olefins has been carried out in an asymmetric fashion catalysed by in situ generated chiral NHC nickel hydride com- 29 plexes of presumed structure (23). Electronic effects of the substrates and the NHC ee 4 Carbenes and Nitrenes 225

ligands account for high chemo- and enantio-selectivity. C2-symmetric six-membered NHC precursors of general structure (24) have been synthesized and engaged in the copper-catalysed conjugate addition of Grignard reagents to 3-methylcyclohexenone.30 Copper–NHC complex (25)(i-PrCuCl) has been reported to catalyse swiftly the fluorination of secondary and even challenging tertiary propargylic positions with an excellent selectivity versus elimination processes commonly associated with this reaction, highlighting the high usefulness of strongly donating ligand for the development of such process.31

Ph Ph N PPh Ph Ph 2 − N BArF4 NN + + Ar Ar′ NN Rh L R R + − N Ni BF4 N PPh2 H R = alkyl, aryl

(22) (23) (24)

Pri Pri

Cu Pri Pri X X = Cl, OTs, OTf (25)

The cationic NHC–iridium complex (26) has shown an unprecedented ability to 32 perform 𝛼𝛼-methylation of ketone using methanol as a methylating agent. The reaction is performed via a hydrogen transfer reaction from methanol to metal, followed by methylenation and reduction of the conjugated alkene. The robustness of the ligand, induced by the nature of the NHC, allows for a catalyst loading of 1%. The use of well- defined nickel–NHC complexes such as(27) enabled the 𝛼𝛼-arylation of ketones from unactivated aryl chlorides at moderate temperatures.33 Owing to the smooth reaction conditions, a wide range of functionalities is well tolerated. A similar iridium complex has been shown to perform primary amide N-alkylation using primary alcohols.34 Nickel complexes featuring the same NHC ligand as (27) have also proved to be excellent catalysts to perform the hydroheteroarylation of alkenes with a large range of pyrroles, furans, indoles, and benxoazoles on terminal, internal, and cyclic alkenes.35 Palladium complexes (28) featuring a NHC with different substituents have been synthesized and tested for the Buchwald–Hartwig amination of chloro and tosylate aromatic compounds.36 Compound (28) featuring a bis-dimethylamino substitution (X = Y = NMe2) proved to be an excellent catalyst, and selectivity for chloro versus tosylate was demonstrated, allowing chemoselective bisamination. 226 Organic Reaction Mechanisms 2015

Copper complexes of 4,5-(9,10-dihydroanthraceno)imidazolin-2-ylidene (29) from their imidazolium precursor were obtained by transmetallation from the silver complexes.37 The rigid scaffold of (29) forces one aromatic ring on the top of the active site and thus provides the features of bulky ligands easing reductive elimination, while smaller substituents on the nitrogen keep the active site accessible. The copper complexes were successfully engaged for the borylation of a range of bromoarenes.

− BArF + Ph Ph Ph Ph NR ′ NN N Ir Ph Ph Ph Ph PR2 Cl

(26) (27)

X Y Pri Pri NN

Pri Cl Pd Pri R Cl N N N R Cl X, Y = H, Cl, NMe2 (28) (29)

Addition–Fragmentations Free Carbenes or Main Group Carbenoids Reactions Additions to C=C double bonds of simple alkenes have been employed as model reactions for examining the reactivity of various carbenes. The reactivity of two highly electrophilic arylchlorocarbenes, pentafluorophenylchlorocarbene and 3,5- dinitrophenylchlorocarbene, has been investigated and compared to the well-established reactivity of phenylchlorocarbene.38 Easily generated by photolysis of their corresponding diazirines, the resulting arylchlorocarbenes have been evaluated for their reactivity toward tetramethylethylene, cyclohexene, and hex-1-ene as model alkenes. From a kinetic viewpoint, 3,5-dinitrophenylchlorocarbene proved to be the more reactive, followed by pentafluorophenylchlorocarbene and finally phenylchlorocarbene, this reactivity order thus not overlapping the order of carbenic stability. Further, 4 Carbenes and Nitrenes 227 based on calculated activation parameters, enthalpy–entropy compensation has been observed in this series of arylchlorocarbenes. Remarkably, the values of activation energies/enthalpies for 3,5-dinitrophenylchlorocarbene constitute the most negative yet encountered in such carbene/alkene addition reactions. A similar study has been carried out on (N-methyl-3-pyridinium)chlorocarbene, thus revealing the highly reactive, electrophilic, and singlet nature of this carbene.39 As to dimethylcarbene, this parent dialkylcarbene has been demonstrated for the first time to express both high reactivity and nucleophilicity in addition reactions to alkenes.40 The formation of three tetracyclic benzene isomers, including the Ladenburg’s prismane and the Loschmidt’s hydrocarbon, has been envisaged by intramolecular carbene additions.41 By means of computational methods, the suggested carbene precursor for the Ladensburg’s prismane proved unsuited to intramolecular cyclopropanation, whereas the potent precursor for the Loschmidt’s hydrocarbon could not be efficiently characterized. The addition of difluorocarbene to= aC C bond has been proposed as a key step in a cascade approach for preparing ortho-fluoronaphthols and ortho-/para- fluorophenols from indanones and cyclopent-2-enones.42 In this cascade process, (bromodifluoromethyl)trimethylsilane (Me3Si–CF2Br) plays a central role not only as difluorocarbene source but also as trimethylsilyl transfer agent as well as bromide and fluoride ions source. A second example of a cascade reaction involving a carbene/alkene addition reaction has been reported.43 The free carbene (31) has indeed been suggested as key intermediate in the mechanistic rationale of the acid-catalysed conversion of electron-deficient ynenones30 ( ) to cyclopropyl-substituted furans (32). The proposed mechanism is quite uncommon due to the participation of a free carbene under acidic conditions (Scheme 2).

R R EWG R R + EWG R H O O R (30) (31)

R R H EWG

O R (32)

Scheme 2 228 Organic Reaction Mechanisms 2015

The formation of (nor)adamantylethylenes (33), resulting from co-photolysis of (nor)adamantyldiazirines and phenylchlorodiazirine, has been mechanistically scrutinized by means of experimental and computational methods.44 Two competitive pathways have been shown to be in agreement with the results obtained both involving the addition of phenylchlorocarbene to a peculiar (nor)adamantyl-based intermediate. The first pathway implicates the addition of phenylchlorocarbene to bridgehead= C C bonds of (homo)adamantenes, whereas the second pathway involves its addition to diazo analogues of (nor)adamantyldiazirines. A carbene/alkene addition reaction has also been utilized as a key step for the synthesis of spirooxindole-dihydrofurans (34) starting from isatins and enones.45 In that work, Kukhtin–Ramirez adducts of isatins (35), considered as equivalents of carbenes (36), have been shown to add to the C=C bond of enones and then lead to spirocyclic (34), thanks to an intramolecular SN2 as final step.

Ph n Cl

(33)

R4 3 R + PPh3 O O

Ar − 1 R1 O R1 O R O N N N 2 R2 R2 R (34) (35) (36)

Addition reactions of carbenes to C=X bonds (X = O, N) have also been reported. endo-Tricyclo[3.2.1.02,4]oct-8-ylidene (37), a foiled carbene generated by thermolysis of its Δ3-1,3,4-oxadiazoline precursor, has been demonstrated to react smoothly 46 with carbonyl compounds, such as benzaldehyde and acetophenone. Remarkably, such de intermolecular reactions proceed with complete diastereocontrol to give regioisomeric products (38) and (39) in the case of benzaldehyde. From a mechanistic viewpoint, these net insertion reactions are believed to arise from a tandem two-step sequence, consisting of a nucleophilic addition of (37) to the C=O bond of the carbonyl compound followed by pinacol rearrangement. The previously reported reaction of diaminocarbenes with aroylimines, furnishing five-membered ring products40 ( ), has been mechanistically investigated by means of computational methods.47 In contrast to prior mechanistic rationales relying on an electrophilic behaviour of diaminocarbenes, the present theoretical study has revealed two alternate and more favourable pathways exploiting here the nucleophilicity of diaminocarbenes. Both mechanistic pathways involve nucleophilic addition of the 4 Carbenes and Nitrenes 229

O O H Ph F3C CF3 Ph H R1 N 2 N 1 R 2HN O R2

(37) (38)(39) (40) carbene to the C=N bond of the aroylimine partner, either on the nitrogen or the carbon atom of the imino group. Diiodomethylmagnesium proved efficient as magnesium carbenoid for adding tothe C=N bond of N-tosylimines, thus furnishing alkyl-𝛼𝛼-iodoaziridines in good to excellent yields.48 Interestingly, the magnesium form has been demonstrated to be more powerful than its lithium equivalent. Diverse C-based Lewis bases, including 1,3-bis(2,4,6-trimethylphenyl)imidazol- 2-ylidene and 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene as NHCs, have been evaluated for their regioselectivity regarding their nucleophilic addition to tetrakis(trifluoromethyl)cyclopentadienone, a well-known ambident electrophilic 49 species. Both NHCs proved to exclusively add to the carbon atom in 𝛼𝛼-position of the carbonyl group of the ketone, thus leading to kinetic products (41). No trace of thermodynamic products (42), resulting from the addition to oxygen atom of the carbonyl group, was detected.

R R N −O N F3C O N + N + F C 3 R CF R 3 − CF3 F3C CF3 F3C CF3 R = 2,4,6-trimethylphenyl or 2,6-diisopropylphenyl (41) (42)

The addition reactions of cyclic (alkyl)(amino)carbene (43) to dihalobis(trimethylsilyl) aminoborane have been examined.50 While the reactions have led to the formation of simple haloaminoborane–carbene adducts (44) starting from chlorinated and bromi- nated aminoboranes, the iodinated equivalent has furnished the cationic iminoboryl- carbene (45) resulting from an oxidative addition at the carbene centre. Only one example of carbene fragmentation has been reported. It is the fragmentation of NHCs (46) equipped with mesitylenyl-like moieties that proved to evolve towards carbodiimide derivatives (47) via 3 + 2-cycloelimination.51 A second equivalent of NHC could then add to (46) to produce unique NHC–carbodiimide adducts (48) (Scheme 3). 230 Organic Reaction Mechanisms 2015

Pri N Pri i N Pr i Pr X = Cl, Br SiMe3 B N X (43) (44)

Pri + N Pri B , I − N

SiMe3 (45)

Transition-Metal-Assisted Reactions Transition metal carbenoids are still widely examined for their high potential to act as cyclopropanating agents. In that way, diverse novel carbenoid sources have been reported. Cyclopropenes have been demonstrated to be powerful zinc vinyl carbenoid precursors, thus furnishing vinylcyclopropane derivatives via their addition to alkenes.52 In addition, the combination of trimethylammonium triflate, n-butyl lithium, and a nickel complex as catalyst has enabled the cyclopropanation of unactivated alkenes.53 The mechanistic rationale for this reaction involves the formation of a nickel carbenoid, further turning into a nickelacyclobutane intermediate via 2 + 2-cycloaddition with the olefinic partner. Two other examples of reactions implying transition metal carbenoids that evolve towards four-membered ring metallacycle intermediates have been reported. First, acetylene–ethylene cross-metathesis towards butadiene has been successfully achieved under Ru-catalysis.54 The use of excess ethylene proved to be pivotal for promoting the reaction in a highly efficient manner. In a similar way, synthesis of 1,4-dienes proved to be achievable by reaction between in situ generated titanium alkenylcarbenoid species and styrenes.55 The cyclopropanation of allylic alcohols has been achieved using a mixture of 56 Nugent’s reagent (Cp2TiCl), diiodomethane, and manganese metal. The allylic de hydroxyl group proved crucial to the reaction, by participating in the formation of the key titanium–carbenoid intermediate. Remarkably, the cyclopropanation occurs in a highly diastereoselective manner with conservation of the native alkene geometry. Several other asymmetric cyclopropanation have also been reported. Aryl-substituted olefins have been efficiently cyclopropanated with ethyl diazoacetate under bothiron and copper catalysis. While an engineered myoglobin-based catalyst proved highly 57 ′ ′ ′′ powerful using iron(II), C2-symmetric planar-chiral-bridged 2,2 :6 ,2 -terpyridines ee (49) have been found efficient under copper(II) catalysis, but with only moderate 4 Carbenes and Nitrenes 231

N N + N N X X X X − (46) N N N • N X = Br, Cl, F, Me Δ

X X X X (47) (48)

Scheme 3 232 Organic Reaction Mechanisms 2015

58 levels of diastereo- and enantio-selectivities. Furthermore, the chiral dirhodium(II) ee tetracarboxylate Rh2(S-DOSP)4 has been found to enable the cyclopropanation of de two alkene/aryl diazoacetate combinations. On the one hand, cis-fluorocyclopropane carboxylates have been obtained with good diastereo- and enantio-selectivities via 59 Rh2(S-DOSP)4-catalysed cyclopropanation of vinyl fluorides with aryl diazocetates. ee On the other hand, the prolinate Rh2(S-DOSP)4 proved to be the best catalyst for promot- de ing the cyclopropanation of styrenes with aryl diazoesters bearing a trimethylsilylethyl group as ester residue.60 Rh(II)-catalysis has also been successfully utilized to cyclopropanate trimethylsily- lacetylene with various crude aryl diazoesters.61 Desilylation of the resulting trimethylsi- lylated cyclopropenes allows the synthesis of 3-aryl-3-methoxycarbonyl cyclopropenes featuring a 1,2-disubstituted olefin moiety. For intramolecular cyclopropanation versions, a series of novel chiral P,N-bidentate ligands (50) has been designed, synthesized, and applied to enantioselective gold- catalysed oxidative cyclopropanation reactions.62 An intramolecular cyclopropanation approach has also been successfully applied to the construction of complex azabicyclo[4.1.0]/[5.1.0] carbaldehydes.63 Starting from N- sulfonyl triazoles equipped with an N-(homo)allyl moiety as azavinyl carbenoid precursors, Rh(II)-catalysis promoted the synthesis of various azabicyclic systems in modest to good yields. Sulfonyl triazoles, especially 4-aryl 1-tosyl 1,2,3-triazoles, have also been employed as rhodium carbenoid precursors and reacted with internal alkynes to furnish complex indeno[1,7-cd]azepine scaffolds (51) via an Rh(III)-catalysed 3 + 2/5 + 2 annulation process.64 The suggested reaction mechanism of this cascade process involves, among others, the nucleophilic addition of the alkyne on the azavinyl carbenoid intermediate.

2 R Ts R2 N PAd2 HO N N N N Ad = adamantyl 1 2 R R R1 R R R2 R2 (49) (50) (51)

N-Sulfonyl triazoles have been found to react smoothly with azirines under Rh(II)- catalysis, thus providing straightforward access to fully functionalized pyrroles.65 Again, the nucleophilic addition, here of the azirine, on the in situ formed azavinyl carbenoid has been proposed as a key step of the reaction mechanism. This strategy has been further applied to the synthesis of URB447 (52), a fully functionalized pyrrole of biological relevance. Structurally related 2-halo-2H-azirines have been found to react similarly with rhodium carbenoids generated from diazo carbonyl compounds.66 After nucleophilic addition of azirine derivatives on the carbenoid 4 Carbenes and Nitrenes 233 species, the resulting azirinium ylide intermediates have been suggested to rearrange to 4-halo-2-azabuta-1,3-dienes with excellent stereoselectivity. Interestingly enough, heating of the so-formed electron-poor azabutadienes has enabled the formation of 2,3-dihydroazetes (53) and 2,5-dihydrooxazoles (54), via 1,4-electrocyclization and 1,5-exo-trig cyclization processes, respectively.

O NH2 2 MeO C R 3 Ph 2 R 5 3 X O R Ph X COR

N N 4 N R1 R O2C R1 Cl (52) (53) (54)

Furthermore, the azavinyl carbene chemistry has been exploited in intramolecular annulation reactions.67 The Rh(II)-catalysed annulation reaction of acyclic oxygen-tethered N-tosyl triazoles (55) led to the formation of 3-methylene-2,3- dihydrobenzofurans (56), whereas 3-methylene-2,3-dihydroindoles (57) have been produced starting from nitrogen-tethered substrates (Scheme 4).

R2 X O N Rh 1 Rh 1 R1 NHTs R R X = O X = NR2 N NN NHTs Ts (56)((55) 57)

Scheme 4

A method for accessing 𝛼𝛼-alkoxy 2H-naphthalenones has been developed starting from N-tosylhydrazones as starting materials, copper iodide as catalyst, and lithium t-butoxide as base.68 The mechanistic rationale starts with the base-mediated formation of a copper carbenoid which next reacts on an ester carbonyl group to furnish alkoxyepoxide (58) as key intermediate. Other species have been used efficiently to trap transition metal carbenoids via nucleophilic addition. Vinyl azides add to gold alkenyl carbenoids generated from propargylic esters,69 while gold vinylidenes proved sensitive to addition of water, thereby generating relevant gold acyl species.70 These gold-catalysed reactions constitute straightforward methods for accessing buta-1,3-dien-2-yl esters from propargyl esters and indene scaffolds from appropriate 1,5-diynes. A further example relying on gold catalysis consists in the intramolecular coupling of bis(diazo carbonyl) compounds leading to macrocyclic 234 Organic Reaction Mechanisms 2015

71 olefins. In that case, a gold carbenoid intermediate generated from one of the two diazo de ketone moieties is trapped by nucleophilic addition of the second diazo ketone moiety. Using this method, macrocycles featuring up to 24-membered rings have been obtained with excellent yields and diastereoselectivities, especially considering the synthetic challenge. A chiral ruthenium/phosphoramide complex has been evaluated as hybrid catalyst for the enantioselective propargylic alkylation of propargylic alcohols with 72 enecarbamates. While the ruthenium centre activates the propargylic alcohol partner ee into an allenylidene-type ruthenium carbenoid, the chiral phosphoramide moiety activates the nucleophilic enecarbamate partner while simultaneously controlling the stereoselective outcome of its nucleophilic addition to the 𝛾𝛾-carbon atom of the native carbenoid species. This example nicely illustrates the concept of cooperative catalysis. The examples treated so far in this section had to do with transition metal carbenoids playing the role of electrophilic species in addition reactions. On the contrary, an example of nucleophilic carbenoid has been reported. The palladium carbenoid complex (59) has indeed been demonstrated to add on B(C6F5)3 via the para-carbon of its supporting ligand, thus resulting in the formation of zwitterionic complex (60).73

PMe3 PMe3 + P Pd P P Pd P R1 OR2 O − B(C6F5)3 (58) (59) (60)

Insertion–Abstraction Free Carbenes or Carbenoids Reactions The metal-free activation of molecular hydrogen by free carbenes is currently a research topic of major current interest. In this context, 1-azulenylcarbene (61), whose peculiar- 74 ity is to exhibit a singlet ground state, has been found to smoothly insert into H2. Interestingly, it has been suggested that the insertion is governed by quantum mechanical tunnelling. Intramolecular C–H insertion reactions remain a powerful tool for accessing relevant organic scaffolds. Accordingly, a direct synthesis of 𝛽𝛽-lactams has been developed, thanks to a 1,4-C–H insertion reaction involving 𝛽𝛽-ketoamides as readily available starting materials.75 The mechanistic rationale suggests the involvement of a free singlet carbene in situ generated by reaction of the 𝛽𝛽-ketoamide with (diacetoxy)iodobenzene in the presence of a base. Similarly, the construction of 3-azabicyclo[3.1.0]hexane scaffolds has been achieved via 1,5-C–H insertion of cyclopropylmagnesium carbenoids generated from judiciously substituted 1-chlorocyclopropyl sulfoxides (62).76 4 Carbenes and Nitrenes 235

Furthermore, 1,3-C–H insertion reactions of various magnesium carbenoids have been theoretically explored using ab initio methods at the B3LYP/6-311++G(d,p) level of 77 theory. The results obtained support a SN2-like mechanism involving the C–H bond as nucleophile and the carbenoid carbon atom as electrophilic centre. Remarkably, the N,N′-diamidocarbene (63) proved able to insert into Si–H bonds of various silanes, without further ring expansion as observed with most of the previously reported carbene–silane adducts.78

3 R R3

N O NN S R1 Cl O O

R2 (61) (62) (63)

Two works dealing with abstraction reactions involving carbenoids have been reported. + On the one hand, the lanthane carbenoid [LaCH2] generated by reaction between bare La+ and propene has been shown to abstract a carbon atom of halobenzenes.79 The so-abstracted carbon atom from the benzene ring, most likely the ipso-position, cou- + pled with the carbene ligand of [LaCH2] to form acetylene. On the other hand, carbon abstraction from the imino-NHC (64) has been performed through its reaction with tetrabenzylhafnium.80 From a mechanistic viewpoint, the resulting hafnium complex (65) is suggested to be formed via three successive benzyl migrations.

Ph i Pr Ph Ph Pri

N Hf N Ph Pri i N N N N Pr Ph Ph

(64)(65)

Transition-Metal-Assisted Reactions Reactions relying on the insertion of transition metal carbenoids into relevant X–H bonds remain well documented. Regarding inert C–H bonds, rhodium carbenoid species in situ generated from 𝛼𝛼-diazomalonates proved able to react with N-phenoxyacetamides to furnish ortho-alkylated phenols (66) as major products.81 In this reaction, the O-NHAc moiety of the substrate plays the role of both directing 236 Organic Reaction Mechanisms 2015 group for the intermolecular C–H insertion step and internal oxidant. The so-formed ortho-quinone methide intermediate (67) is finally trapped by methanol as protic solvent and nucleophilic partner to provide (66). Intramolecular C–H insertion reactions have also been employed to construct important cyclic compounds. On the one hand, the construction of 3-iodo-1-substituted-1H-indenes has been accomplished starting from iodoalkynes (68) under gold(I) catalysis.82 The suggested mechanistic rationale involves the intramolecular C–H insertion reaction of gold iodovinylidene intermediates (69) as a key step.

OH O R2 CO R 1 2 CO2R R OMe RO2C RO C 2 I (66)(67)(68)

+ R2 R1 Au •

(69)

On the other hand, the synthesis of 2,3-disubstituted pyrans (70) has been achieved via a 1,6-C–H insertion step starting from 5-allyloxy-2-diazopentanoates (71) and 83 using dirhodium(II) carboxylates as chiral catalysts. Excellent levels of diastereo- de and enantio-selectivities have been reported under the optimized reaction conditions. ee Similarly, pyrans have been obtained under asymmetric copper(II) catalysis via a 1,6-O–H insertion reaction using C2-symmetric planar [2.2]-paracyclophane-based bisoxazolines as chiral ligands.84

CF3 CO2Me CO Me 2 R R N2 O O Ph CF3

(70) (71) (72)

Using the novel C1-symmetric diene (72) as chiral ligand, rhodium(I) catalysis has been demonstrated to promote the asymmetric insertion of 𝛼𝛼-diazo carbonyl compounds into the B–H bond of readily available amine–borane adducts.85 ee 4 Carbenes and Nitrenes 237

Transition-metal carbenoid migratory insertion reactions attract an ever-increasing interest in organic chemistry. Several novel palladium-catalysed methods have been developed by exploiting this tool as a key step. Formal palladium carbenoid insertion into C–H,86 C–N,87 Si–Si, and 88 Sn–Sn bonds have thus been achieved with either N-tosylhydrazones or 𝛼𝛼-diazo esters as carbenoid precursors. Cross-coupling reactions, including alkyne–alkyne coupling,89 and coupling between electron-poor aryl fluorides and N-tosylhydrazones90 have been described, as well as the construction of benzofused carbo- and hetero-cycles (indanes, benzofurans, and indenones).91 Similarly under rhodium catalysis, the C–H functionalization of 2-arylbenzo- 92 93 thiazoles, and 𝛼𝛼-imino Csp3 –H bonds, with 𝛼𝛼-diazo esters has been reported in parallel, while the C–C bond insertion reaction between benzocyclobutenol and diazo esters has been theoretically investigated by means of DFT calculations.94 Rhodium- catalysed Stille-type coupling of aryl stannanes and diazo esters,95 and also the three- component coupling reactions of t-propargyl alcohols, alkyl halides, and diazo esters,96 has been developed and suggested to occur via carbenoid migratory insertion. Further- more, 1,2-benzothiazine,97 and 3H-indole-N-oxide,98 heterocyclic scaffolds have been constructed via intramolecular processes, starting from S-aryl sulfoximines and nitrones. Both processes mechanistically involve a rhodium carbenoid insertion as a key step. Other miscellaneous examples exploiting carbenoid migratory insertions have been reported with copper to generate allenes,99 or quaternary centres100, silver for trifluoroethylation,101 cobalt102 or iridium103 for aromatic C–H functionalization, and zinc or cadmium promoting methylenation of an NHC.104

Rearrangements Free Carbenes or Carbenoids Reactions 1,3-Dimethylimidazolin-2-ylidene NHC and tritylcarbenes have been shown to undergo intramolecular ring-expansion reactions. On the one hand, vacuum ultraviolet (VUV) photoexcitation of the NHC has given rise to the formation of two six-membered ring products, namely methyl-pyrimidinium (73) and methyl-pyrazinium (74) ions.105 On the basis of mechanistic investigations led by means of experimental and theoretical methods, the initial intramolecular hydrogen transfer to the NHC carbon has been found to be the crucial and kinetically limiting step, thereby affording imidazolium ions (75) and (76) as key intermediates.

+ + + NN N N N N N N +

(73) (74) (75) (76)

On the other hand, heptafulvenes (77) have been identified as by-products during the rearrangement of tritylcarbenes.106 DFT and ab initio calculations have supported 238 Organic Reaction Mechanisms 2015 the participation of fused bicyclobutanes (78) as key intermediates for heptafulvenes formation. The phototriggered diphenylcarbene to fluorene rearrangement has been scrutinized by UV–vis, IR, and EPR spectroscopies.107 The results obtained have enabled the identification of allenic 1-phenyl-1,2,4,6-cycloheptatetraene79 ( ) as key intermediate which was missing in previously suggested mechanisms of this rearrangement. Trifluoromethylphenylcarbenes, in situ generated by photolysis or flash vacuum thermolysis of their diazirene or diazomethane surrogates, have been demonstrated to rearrange to trifluorobenzocyclobutene, trifluorostyrene, and trifluoromethyl- fulvenallenes.108 The NHCs of indazole, namely indazol-3-ylidenes, have been shown to undergo ring opening via the cleavage of their N–N bond, thus furnishing transient N-(6- methylenecyclohexa-2,4-dien-1-ylidene)anilines (80).109 Further trapping of (80) by alcohols allowed the formation of few reported 1-anilinobenzimidates.

NR2 • Ar Ph R Ar 1 Ar R NR Ar (77) (78) (79) (80)

Rearrangement of diverse 𝛾𝛾-trimethylsilyl-substituted carbenes has been investigated by means of experimental and computational methods.110 In the case of acyclic substrates, 1,3-trimethylsilyl migration proved to be in competition with 1,3-hydrogen migration to the carbene centre. The case of cyclic substrates strongly differs with that of acyclic substrates, only [1,n]-hydrogen migration processes taking place with cyclic substrates. While [1,2]-hydrogen migration predominates with five-membered ring, [1,3]-hydrogen migration has been shown to occur with six- and seven-membered rings.

Nucleophilic Carbenes–Carbenes as Organocatalysts Transformations Mediated by Breslow-Type Intermediates Umpolung reactions of carbonyl compounds involving Breslow-type intermediates continue to be highly studied and exploited in organic synthesis. A study of the archetypical NHC-catalysed Stetter condensation reaction has revealed for the first time that the reactivity profile in the gas phase contrasts with thatin solution.111 Significantly, the key umpolung step leading to the Breslow intermediate is problematic in the gas phase but this could nevertheless be circumvented by the use of acylsilanes as carbonyl surrogates. Benzoin and cross-benzoin condensation reactions remain relevant umpolung reactions, mainly studied for their selectivity and scope of applications. The benzoin reaction has been used as model reaction to computationally evaluate the potential of a series 4 Carbenes and Nitrenes 239 of NHCs as umpolung catalysts.112 Thus, 19 NHCs of various types (i.e. (ab)normal, remote, and reduced heteroatom stabilized) have been theoretically explored in the benzoin reaction using ab initio methods at the CPCM-B3LYP/6-311+G(d,p)//B3LYP/6- 311+G(d) levels of theory. Overall, the abnormal pyridyl-3-ylidene NHC (81) has been found to exhibit the best reactivity profile as catalyst in the benzoin reaction. In a similar way, the formation of Breslow intermediates by reaction between benzaldehydes and N-aryl triazolium salts as NHC precursors has been examined from kinetic and thermodynamic viewpoints.113 Rate and kinetic measurements have been experimentally determined for a series of NHC/benzaldehyde combinations. The results obtained have revealed the highly valuable effect of the benzaldehyde 2-substituent in this reaction, thus giving further insight into the chemoselectivity of cross-benzoin reactions. Another work dealing with the chemoselectivity of triazolium-catalysed cross- benzoin reactions has been reported.114 On the basis of computational and 1H NMR results, the chemoselectivity of cross-benzoin reactions implicating triazolium salt (82) as NHC precursor proved to be under kinetic control. A DFT study has also been led in parallel on such reactions and has disclosed additional key elements related to their mechanism and chemoselectivity.115 In terms of applications, an NHC-catalysed benzoin approach has been developed for the enantioselective synthesis of tertiary alkynyl 116 carbinols. The chiral triazolium salt (83) proved to be the best pre-catalyst for achiev- ee ing the reaction between (hetero)aryl aldehydes and ynones with excellent yields and enantiomeric excesses. Novel NHC-catalysed methods involving Breslow intermediates have also been developed for the functionalization of relevant building blocks, such as aldehydes or enals. The oxidative enantioselective 𝛼𝛼-fluorination of aliphatic aldehydes has been accom- 117 plished for the first time via NHC catalysis. In the presence of chiral triazolium salt ee (84) as pre-catalyst and N-fluorobis(phenyl)sulfonimide (NFSI) as oxidant and fluorine source, the expected 𝛼𝛼-fluorinated esters have been obtained in excellent yields and good enantioselectivities, without any trace of difluorinated side products. Mechanistically, the intermediate Breslow species is suggested to be oxidized by NFSI to an acyl azolium, prone to be 𝛼𝛼-fluorinated via its enolate form. Three NHC-catalysed methods allowing the 𝛽𝛽-functionalization of enals have been reported. The highly enantioselective 𝛽𝛽-hydroxylation of enals has been achieved using chiral triazolium salt (82) as pre-catalyst and nitrobenzenesulfonic carbamate (85) as 118 oxidant. The mechanism has been investigated using control experiments and by ee means of EPR spectroscopy, thus suggesting a radical pathway involving successive single-electron-transfer steps. The 𝛽𝛽-protonation of enals has also been accomplished in a highly enantioselective manner.119 The so-developed method relies on cooperative catalysis between three distinct organocatalysts, namely N,N-dimethylaminopyridine as nucleophilic catalyst and squaramide as H-bond donor catalyst (86) in addition to chiral triazolium salt (87) as NHC precursor. The third reported method is related to the 𝛽𝛽-functionalization of 120 Baylis–Hillman enals. C-functionalization of 𝛼𝛼-cyanocinnamaldehydes by phenacyl bromide has been accomplished using benzimidazolium salt (88) as pre-catalyst, and the resulting amide adducts were efficiently cyclized to 𝛿𝛿-lactams via an iodine-catalysed process. 240 Organic Reaction Mechanisms 2015

N + R BF − O + − N 4 N N + N N C6F5 R R N − BF4

(81) (82) (83) R = Me (84) R = Br

EtO2C O2 N S O

O2N (85)

F C O O CF 3 3 N O + N N N N H H F C CF BF − 3 3 Ph 4 (86) (87)

Ph N + Cl− N Ph (88)

Diverse annulation methods exploiting Breslow species as key intermediates have been described. An NHC-catalysed 3 + 4 annulation process between enals and aurones has 121 been developed using chiral bifunctional triazolium salt (89). Under the optimized de conditions, the annulated products, namely benzofuran-fused 𝜀𝜀-lactones (90), have been ee obtained in good yields and excellent diastereo- and enantio-selectivities. The annulation reaction furnishing tricyclic sulfonyl amides (91) through oxidative NHC-catalysed reaction between enals and imines has been mechanistically investigated.122 The experimental results have revealed that all steps of the mechanism, including the oxidation of the Breslow intermediate, are favoured, except the formation of the Breslow intermediate which proved to be the rate determining step of the process. Interestingly enough, the tricyclic products (91) have been shown to exhibit promising antimicrobial activities. A method for accessing highly substituted indeno[2,1-b]pyrroles (92) has been elaborated by reaction between ynals and thiazolium salts (93).123 Remarkably, thiazolium salts (93) play a dual role in the reaction, both as pre-catalyst and reaction partner. 4 Carbenes and Nitrenes 241

R1 N + N O 2 N O R O i Pr EtO2C N F3C − BF4 OH O SO2 2 3 F3C Ar R Ar1

F3C CF3 (89) (90) (91)

2-Bromoenals remain relevant building blocks for performing NHC-catalysed annulation reactions. The enantioselective synthesis of dihydropyridines has been achieved through a 3 + 3 annulation process between 2-bromoenals and aldimines using the enan- 124 tiomer of (83) as pre-catalyst. The reaction of 2-bromoenals with 3-aminooxindoles ee has been found to furnish spirooxindole 𝛾𝛾-butyrolactams (94) through an NHC-catalysed 125 3 + 2 annulation process. The method proved to be highly enantioselective using the ee chiral triazolium salt (95) as NHC precursor.

Ar R N + Z X − R1 N R2 S HO O (92) (93)

BocN N + 2 N R N R1 O N Ph Cl −

(94) (95)

In a similar way, an NHC-catalysed method for synthesizing spirocarbocyclic oxindoles (96) has been set up by reaction of 2-bromoenals with 3-alkylenyloxindoles.126 The enantiomer of (83) has been further reported as an efficient precatalyst in two annulation reactions relying on NHC-redox catalysis. While trichloromethylated syn-dihydropyranones (97) have been prepared in a highly stereoselective fashion via a4+ 2-hetero Diels–Alder using 𝛼𝛼,𝛽𝛽-unsaturated trichloromethyl ketones as starting materials,127 this chiral triazolium salt also proved to promote the enantioselective 128 synthesis of fluorinated oxetanes via a2 + 2 annulation process. ee 242 Organic Reaction Mechanisms 2015

Two last examples of a reactions mediated by a Breslow intermediate, especially a deoxy-Breslow intermediate, have been reported. The first one concerns the transfer hydrogenation of electron-poor C=C, C=N, and N=N bonds.129 In that case, the NHC (98) acts as stoichiometric reducing agent, whereas water plays the role of proton source. The second example deals with the synthesis of 𝛼𝛼,𝛽𝛽-epoxy ketones through an NHC- catalysed oxidative coupling between styrenes and aldehydes.130 Mechanistic studies have suggested the involvement of a ketodeoxy Breslow intermediate.

R1 O Ph 1 R N EtO2C N R3 O O 2 N O R CCl3 Ph N Ph R2 (96) (97) (98)

Transformations Non-Mediated by Breslow-Type Intermediates The number of catalytic reactions exploiting the nucleophilicity of NHC in a non-Breslow fashion continues to increase. Several annulation reactions furnishing biologically relevant scaffolds have been 131 132 investigated. Benzothiazolo-pyrimidinone- and dihydrocoumarin- based scaffolds ee have been constructed in an asymmetric fashion, both using triazolium salt (95) as precursor of the active nucleophilic NHC catalyst. The chemoselective formation of pyranyl aldehydes (99) via NHC-catalysed reactions between allenals and chalcones has been studied computationally.133 The theoretical results reveal that the most energetically favourable pathway starts by the nucleophilic addition of the NHC on the centre carbon atom of the allene moiety rather than on the carbonyl group of the allenal. Thus, the involvement of the resulting non-Breslow intermediate has gone on providing crucial insights on the unexpected chemoselectivity related to such reactions. A mechanistic study has also been conducted on the NHC-catalysed version 134 of Staudinger reactions furnishing trans-𝛽𝛽-lactams. According to the experimental de results obtained, a mechanism could be suggested for this formal 2 + 2-cycloaddition process, and the diastereoselectivity proved to be highly dependent on the steric bulk of the NHC catalyst and the nature of the solvent. Annulation methods via intramolecular NHC-catalysed processes have also been developed. Using commercially available 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (IMes) as pre-catalyst, chromenes have been accessed from 2-(buta-2,3- dienyloxy)benzaldehydes (100), whereas their homologue allenals (101), namely 2-(propa-1,2-dienyloxy)benzaldehydes, have yielded chromones under similar reaction conditions.135 From a mechanistic viewpoint, chromenes have been suggested to result from a formal hydroarylation process and chromones from a hydroacylation one. This divergent reactivity has been further rationalized by means of DFT calculations. 4 Carbenes and Nitrenes 243

1 2 R R N OMe CHO O + N O R N OHC • O n MeO − 3 4 BF4 R R (100) n = 1 Ph (99) (101) n = 0 (102)

Another intramolecular hydroacylation method has been developed for accessing chiral cyclic ketones.136 The so-developed hydroacylation of unactivated alkenes employs triazolium salt (102) as the best pre-catalyst and exhibits a wide scope and compatibility with functional groups. NHC-catalysed conjugated additions are also gaining ground. Extensive mechanistic studies have been led on the NHC-catalysed conjugated addition of diboron and borosi- 137 lane reagents on 𝛼𝛼,𝛽𝛽-unsaturated carbonyl compounds. On the basis of the experimental and theoretical results, stereochemical models have been proposed to rationalize the stereoselectivity of such reactions. The nucleophilicity of NHC, in particular Imes, has 138 been successfully exploited for the synthesis of 𝛿𝛿-sultones of medicinal relevance. The elaborated method involves a conjugated addition of an in situ generated enolate on an intermediary Michael acceptor, that is an 𝛼𝛼,𝛽𝛽-unsaturated sulfonyl azolium salt formed by the nucleophilic addition of IMes on the starting sulfonyl chloride. Other formal conjugate addition reactions have been described using NHC as non-nucleophilic catalysts. While the NHC-catalysed synthesis of 𝛾𝛾,𝛾𝛾-disubstituted butenolides (103) possessing adjacent tertiary and quaternary carbon atoms has been accomplished using the NHC as a strong Lewis base,139 chiral trifluoromethylated amines (104) have been synthesized via an aza-Michael addition reaction promoted by the NHC (83) as a non- 140 covalent catalyst. ee

EWG 1 2 R F3C R MeN NMe O O NO2 R1HN R2 Si Si t t Bu 3Si H Bu 3Si H (103) (104) (105) (106)

The asymmetric aminomethylation of enals has been accomplished via NHC- and in situ-generated Brönsted acid-cooperative catalysis, affording challenging 𝛽𝛽2-amino 141 acids in excellent yields and stereoselectivites. The proposed reaction mechanism ee involves a non-Breslow azolium enolate species as key intermediate. H/D exchange reactions between pseudoacids (pKa,DMSO = 14–19) and deuterated chloroform have been promoted by 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene as stable and commercially available NHC catalyst.142 On the basis of experimental and theoretical results, a stable azolium-trichloromethyl anion Brönsted pair has been suggested as key intermediate. 244 Organic Reaction Mechanisms 2015

Nitrenes Free Nitrenes – Generation and Reactivity A nitrene transfer method has been developed for the direct amination of arenes.143 Var- ious simple arenes have been successfully aminated using aryl sulfonyl azides as nitrene source under solvent-free conditions at 130 ∘C. Another intermolecular nitrene transfer approach has been reported for the synthesis of polysubstituted 2-aminopyrroles.144 The approach comprises a formal 3 + 2- cycloaddition process via gold-catalysed nitrene transfer from vinyl azides to ynamides. From a mechanistic viewpoint, the participation of a nitrene or its corresponding 2H-azirine as key intermediate has been investigated, the obtained results supporting the 2H-azirine pathway. The reaction of triplet phenyl nitrene with molecular oxygen has been studied in detail.145 Under optimized reaction conditions, the phenyl nitrene, smoothly generated by flash vacuum thermolysis, proved to react with molecular oxygen to furnish the nitroso O-oxide derivative, which further rearranges to nitrobenzene under light.

Transition-Metal-Assisted Reactions The insertion of transition metal–imides (i.e. nitrenoids) into C–H bonds remains a tactic of choice for C–N bond formation. Using this tactic, the synthesis of quinolin- 8-ylmethanamines has been achieved under Ru(II)-catalysis from readily available 8-methylquinolines and aryl sulfonyl azides as nitrenoid source.146 This method corresponds to the first example of [(p-cymene)-RuCl2]2-catalysed Csp3 –H bond intermolecular amidation reaction. The mechanism of diverse C–H insertion reactions has been explored computationally. 147 Regarding Csp2 –H activation reactions, the copper-catalysed amination of benzene and the chemoselective gold-catalysed amination of mesitylene148 have been studied by means of computational methods, and the results of both studies have supported a nitrene addition pathway. A mechanistic study has also been led on the Rh(III)-catalysed Csp2 –H activation/cycloaddition of benzamide and diazo compounds.149 Using DFT calculation methods, an Rh(V)-nitrenoid species has been identified as key intermediate of this relevant transformation. A range of ‘nitrene radicals’ have been described as relevant species appearing in the course of porphyrin–cobalt-catalysed nitrene transfer reactions.150

Heavy-Atom Carbene Analogues

Reaction of 2,5-dihydrofuran with silylene (SiH2) generated by Laser flash photolysis of phenylsilane has been kinetically studied in the gas phase. Although no end product could be identified by GC, second-order kinetics were obtained and ab initio calculation predicted reactivity to take place at oxygen or on the double bond.151 NHC-stabilized silylene (105) was shown to undergo a 2 + 2 + 1 addition with 2 equiv of phenylacetylene.152 The silole product (106) has been fully characterized, and the reaction path has been thoroughly studied by DFT calculations. 4 Carbenes and Nitrenes 245

Photochemical reaction of azulene and guaiazulene with silylene (107) provided single products, one corresponding to an Si insertion into the five-membered ring of the guaiazulene (108) and one featuring a similar insertion plus one cycloadduct (109) on the less sterically demanding azulene.153

TMS TMS TMS TMS TMS TMS

Si TMS Si Si TMS TMS TMS Si TMS TMS TMS TMS i Pr TMS (107) (108) TMS (109)

Kinetic and computational studies of the reaction of dimethyl- and diphenyl- germylenes with oxiranes and thiiranes have been performed, allowing the identification of equilibrated reactions and their kinetic constants.154 Silathiogermylene (110) generated from the corresponding chlorogermylene (111) was shown to yield germaacid anhydrides (112) in its reactions with elemental chalcogens.155

But But But But N N N N X Ge Ge Ge Ge SSiMe Cl N X N N 3 N X But But But But X = S, Se (110) (111) (112)

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