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Catalysis of Organic Processes by Metal Phenolates

Metal Phenolates (2013)

  1. Maria Silva Serra,
  2. Dina M. B. Murtinho

Published Online: 14 DEC 2012

DOI: 10.1002/9780470682531.pat0610

Patai's Chemistry of Functional Groups

Patai's Chemistry of Functional Groups

How to Cite

Serra, M. S. and Murtinho, D. M. B. 2012. Catalysis of Organic Processes by Metal Phenolates. Patai's Chemistry of Functional Groups. .

Author Information

  1. Faculty of Science and Technology, University of Coimbra, Department of Chemistry, Coimbra, Portugal

Publication History

  1. Published Online: 14 DEC 2012

1 Introduction

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References

Metal phenolate catalysts encompass an extensive variety of complexes both regarding the metal and the ligand type. Phenols are important and versatile groups in organic synthesis because their aromatic moiety can be sterically and electronically modified giving rise to a great variety of ligands. This opens the door to a myriad of structurally diverse phenolate-containing catalysts with appropriate characteristics of reactivity and selectivity for promoting innumerous transformations of synthetic interest in organic chemistry. Metal phenolates have thus become essential participants in catalytic organic synthesis, including catalytic asymmetric synthesis. Among the reactions promoted by these catalysts are oxidations of alkenes, sulfides, alcohols and alkanes, additions of trimethylsilylcyanide, diorganozincs and nitroalkanes to C[DOUBLE BOND]O and C[DOUBLE BOND]N bonds and Diels–Alder reactions.

The purpose of this chapter is to provide an overview of recent advances, especially in the last decade, in the catalysis of organic processes by metal phenolates. The limitations of space make it impossible to consider in detail all of the organic processes. Consequently, greater emphasis will be placed on the reactions which are most frequently catalyzed by metal phenolates.

2 Oxidations with Metal Phenolates

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References

2.1 Epoxidations

Among the key reactions in organic chemistry are the oxidations of alkenes to epoxides. The importance of this type of reaction is due to the versatility of the product epoxides, as intermediates in the synthesis of an extensive variety of compounds through ring opening reactions with appropriate reagents. Moreover, chiral epoxides are especially significant for being building blocks in the synthesis of enantiomerically pure biologically active molecules, among which are pharmaceuticals and agrochemicals1, 2.

Epoxidation of alkenes with organic hydroperoxides, hydrogen peroxide or hydrogen peroxide complexes (equation 1), is carried out in the presence of a transition metal catalyst. Many transition metal complexes have been used as catalysts in the epoxidation of alkenes, namely manganese, vanadium, titanium, rhenium, ruthenium, tungsten, cobalt, iron and molybdenum, among others1-5. However, molybdenum complexes are considered the best and most versatile catalysts for the epoxidation of alkenes, having longstanding application in oxidations by organic hydroperoxides6.

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Many structurally different complexes have been synthesized and used as homogeneous catalysts for the epoxidation of alkenes. This diversity arises from the metal as well as from the organic ligand used. The ligands may be of different classes, which implies the existence of different types of coordinating atoms and, depending on the number of these atoms, they may exhibit bi-, tri- or tetradentate coordination.

The chemistry of Schiff base ligands and their metal complexes has received significant attention due to their structure and catalytic activities, including mimicking enzymatic hydrocarbon oxidation. Schiff base ligands are easily prepared by the condensation of readily available amines with aldehydes or ketones. Among many catalytic systems, the molybdenum(VI) Schiff base catalysts have surfaced as a powerful alternative for the oxidation of unfunctionalized alkenes. Tridentate {ONO} dioxomolybdenum Schiff base complexes 1–3 have been used by Rezaeifard and Bagherzadeh, among others, in the epoxidation of cyclic and linear alkenes7-12. Using 1–2 equivalents of t-BuOOH and 1 mol% catalyst containing {ONO}-type ligands, substrates were oxidized in 1,2-dichloroethane (1,2-dce) at 80 °C in a short reaction time, with excellent conversions and complete selectivity for the formation of epoxide. The most active catalysts were those with bulky, electron-poor substituents on the salicylaldehyde moiety, namely when X and Y are t-butyl groups (e.g. 1d). Retention of the starting olefin configuration was observed for the epoxide in the presence of these tridentate Schiff base ligand complexes. On the other hand, both molybdenum and tungsten complexes 3, with the cyclohexyl backbone, gave very low conversions to epoxide11.

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Oxa-bridged bis(oxovanadium) complexes 4 with tridentate {ONO} Schiff bases were used in the epoxidation of cyclooctene with t-BuOOH under solvent-free conditions. Complex 4c was found to be the most efficient, giving almost complete conversion of the substrate with 83% selectivity for the epoxide. With H2O2, however, no oxidation occurred13. With the equivalent MnIII complex of 4c, using urea–hydrogen peroxide (UHP) as the oxygen source in MeOH/dcm at room temperature, epoxides were formed in 60–90% yields from aryl–linked alkenes14. The presence of imidazole as co-catalyst was found to be essential for the successful oxidation by UHP.

RuII complexes of tridentate {ONO} and {NNO} Schiff bases 5 and 6 have been used by Chatterjee and coworkers2, 15 for the room-temperature epoxidation of styrene and derivatives with t-BuOOH and 1 mol% catalyst in dcm. All complexes exhibited similar activity and, although epoxides were always the major products, minor amounts of aldehyde were also obtained. The same authors used ruthenium complexes of chiral Schiff base ligands 7, derived from l-amino acids (l-tyrosine, l-histidine, l-phenylalanine, l-alanine) and substituted salicylaldehydes, to catalyze the asymmetric epoxidation of alkenes2, 16-18.

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With styrene and derivatives, in the presence of iodosylbenzene as terminal oxidant, moderate conversions and ee were obtained, with the histidine derivative 7 (R = 2-imidazolylmethyl), yielding up to 75% ee of the (S)-epoxide.

A novel family of ruthenium(III) complexes 8 and 9 of a tridentate chiral Schiff base ligand obtained from condensing d-glucosamine with 3,5-di-t-butylsalicylaldehyde was also reported by Chatterjee2, 18-22. In the presence of 1 mol% of these complexes, the epoxidation of alicyclic and aryl–linked alkenes in dcm with t-BuOOH at room temperature occurs with moderate yields, good selectivity for epoxide and ee up to 94%. In these systems, while the chiral ligand controls stereoisomeric induction, the reactivity of the catalyst is dependent on the bipyridine, triphenylphosphine and amino acid ligands.

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Complexes 10 and 11, analogues of 8 and 9, were used by Zhao and coworkers23, giving moderate epoxide yields with t-BuOOH at 55 °C in toluene. Contrary to the ruthenium complexes, however, low ee are obtained for the product, the highest being 30% in the epoxidation of β-methylstyrene.

Sui and collaborators used dioxomolybdenum(VI) complexes 12 derived from tris(hydroxymethyl)aminomethane which coordinate in a tridentate {ONO} manner to catalyze the epoxidation of cyclohexene with t-BuOOH in 1,2-dce at 80 °C24. Although high conversions and selectivity were observed with all the catalysts tested, 12d, with an electron-withdrawing NO2 on the ligand, was found to be much more effective.

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Hydrazone Schiff base complexes have shown interesting results in the epoxidation of alkenes25-27. A distinctive feature of these ligands is that they can behave as bi-, tri- or tetradentate, depending on the nature of the heterocyclic ring, allowing for complexes of very diverse structures. The catalytic potential of complexes of this type, 13 and 14, has been tested using H2O2 as oxidant and 0.25 mol% catalyst in acetonitrile at 60 °C. With mono-oxovanadium(V) complexes of 13 and various terminal, cyclic and phenyl substituted alkene substrates, good to excellent conversions were obtained. However, complete selectivity for the epoxide was only observed for cyclooctene. The vanadium-13a catalyst, with R1 and R2 = H, was the most efficient while less active species resulted from ligands 13b and 13c, with electron-donating substituents25.

With the analogous FeIII complex of 14b, Monfared, using the same substrates, obtained similar conversions, and additionally, for most of the substrates a high selectivity for the epoxide. Under the same reaction conditions, the presence of imidazole as co-catalyst in a imidazole:catalyst ratio of 33:1 enhances the activity of the catalyst26. The MnIII complex of 14a was tested by Pouralimardan and coworkers27 in the epoxidation of cyclohexene, using PhIO as the oxidant in acetonitrile at 32 °C. With 1 mol% catalyst and imidazole as co-catalyst (10:1), conversions of up to 84% and complete selectivity for the epoxide were observed. In the absence of imidazole, other products besides the epoxide are formed.

The dioxomolybdenum(VI) complex 15 of a bidentate {NO} Schiff base was used in the epoxidation of cyclic and linear alkenes by Bagherzadeh and collaborators12. In the presence of 1 equivalent of t-BuOOH and 0.02 mol% catalyst, substrates underwent fast oxidation in 1,2-dce at 80 °C, with high conversions and complete selectivity for the formation of epoxide. When aromatic substrates were used, however, both yield and selectivity were low.

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Zhou and coworkers synthesized and tested a variety of bidentate {NO} methyltrioxorhenium(VI) Schiff base complexes 16 in epoxidation reactions28, 29. Cyclooctene, 1-octene and styrene were oxidized in the presence of 30% H2O2 and 1 mol% catalyst at room temperature. With the exception of styrene, almost quantitative conversions were obtained with exclusive formation of epoxide. Catalysts with electron-donor substituents (16d,16e,16h) on the aniline moiety showed reduced activity and low stability. On the other hand, in the presence of electron-withdrawing groups (16b,16f), catalysts display high activity and selectivity.

Traar and coworkers prepared several bidentate {NO} oxorhenium(V) complexes of pyrazole-based phenoxide 17 and tested their ability to epoxidize alkenes30. Using t-BuOOH in chloroform at 50 °C in the presence of 2 mol% catalyst, moderate conversions were obtained for cyclooctene, the epoxide being formed exclusively. No significant difference in activity was observed related to the methyl group substituents.

Gharah and collaborators used complexes of aldoximes, bidentate ligands which bear some structural similarity to Schiff bases, to catalyze the epoxidation of alkenes31, 32. Molybdenum oxodiperoxo complexes of 18 brought about almost quantitative conversions and selectivity in the epoxidation of a variety of alkenes with 30% H2O2 in MeCN and NaHCO3 as a co-catalyst, at room temperature. The presence of the co-catalyst is essential for the successful use of the ‘green’ oxidant. The tungsten(V) complex of 18b was found to be more active than its molybdenum analogue.

Amine trisphenolates are particularly interesting and versatile tetradentate {NOOO} ligands. Their structures can be modulated in order to change electronic and steric properties of the corresponding metal catalysts33. Transition metal ions such as MoVI, VV and FeIII, give rise to complexes endowed with catalytic properties for various processes34-36. Oxomolybdenum(VI) complex 19 has been used to oxidize cyclooctene, cyclohexene and linear aryl and non-aryl–linked alkenes. Reactions were carried out at 60 °C, in 1,2-dce with cumyl hydroperoxide or t-BuOOH in methanol with 35% H2O2 as the oxidant. The most efficient system was 19/t-BuOOH, while no reaction occurred when the oxidant was H2O2. Selectivities were mostly excellent for epoxide formation and yields were better than 70%. With linear alkenes as substrates, although selectivity remained very high, conversions were slightly lower34.

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Epoxidation of styrene and trans-stilbene was carried out by Groysman and coworkers35, t-BuOOH at room temperature in dcm, catalyzed by 5 mol% vanadium amine trisphenolate complexes (20). The reactions were extremely slow and epoxide was the only product formed from trans-stilbene but not from styrene.

Epoxidation of styrene with t-BuOOH in refluxing toluene was attempted using as catalyst 5 mol% FeIII complexes 21. Conversions were modest (45–55%), no significant difference being observed between the various derivatives. As with the vanadium complexes (20), epoxide was the dominant but not the exclusive product36.

Bisamine phenolates and amine bisphenolates are tridentate{NNO} and {NOO}-type ligands, respectively, which display great structural diversity37-39. Mitchell and coworkers studied the oxidation of (4-methylpent-3-enyl)benzene and some of its derivatives with molybdenum and tungsten complexes 22 and their corresponding dimers (X = μ-O), in the presence of 2.5 mol% catalyst and t-BuOOH in toluene at 30–60 °C, with conversions of at least 75% and high selectivity38. Both the MoVI and the WVI complexes of the bisamine phenolates with R ≠ H gave moderate but highly selective conversions in the epoxidation of styrene. Complexes 22 showed retention of configuration in epoxide formation, with respect to the starting olefin37.

Wong and coworkers presented a series of dioxomolybdenum(VI) and dioxotungsten(VI) complexes 23 with {NNOO}-type ligands40. These ligands have a similar amine bisphenolate core, differing in the N-heterocyclic group bonded to the nitrogen, namely a pyridyl, benzimidazolyl or quinolinyl, which constitute the fourth coordinating group. The catalytic activity of these complexes in the epoxidation of styrene was studied. Reactions were carried out with t-BuOOH and 2.5 mol% catalyst in toluene, at 65 °C. Yields up to 56% were obtained, those with molybdenum complexes being slightly higher than with the tungsten analogue.

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Traar and collaborators39 also recently described {NNNO} and {NOOO} ligands with four donor atoms that could possibly coordinate in a tetradentate manner. Despite this fact, crystallographic and spectroscopic studies proved that in oxidorhenium(V) complexes 24 and 25 these ligands coordinate only in tridentate fashion, leaving the fourth group with the donor atom as a dangling ligand. These complexes were tested in the epoxidation of cyclooctene with a 3-fold molar excess of t-BuOOH and 2 mol% of the catalyst, in chloroform at 50 °C. All catalysts gave conversions to the epoxide in the 50–55% range.

The catalytic activity seems, therefore, to be independent of the ligand. Furthermore, these catalysts were inactive in the presence of H2O2 as well as toward other alkenes.

Immobilized catalysts have received noteworthy attention due to advantages in the use of this type of catalyst over homogeneous catalysts. Immobilized catalysts can combine the high activity, selectivity and reproducibility of homogeneous catalysts and the easy separation, recovery and stability to allow for catalyst recycling of heterogeneous catalysts. A great variety of organic, inorganic and more recently hybrid organic–inorganic supports have been used for immobilization. Supported Schiff base–metal catalysts have been the most widely studied for epoxidation of alkenes. Among the organic supports, poly(styrene-divinylbenzene) has been the most frequently used. t-BuOOH acts as oxidant (H2O2 or oxygen may also be used) in the presence of metal complexes of immobilized Schiff base ligands 26–29 or complex 30, at temperatures in the 60–100 °C range. Most of the metal complexes show high catalytic activity and selectivity for epoxide formation, many being more active than their unsupported counterparts. Attempts to recycle this type of catalyst showed that in some cases up to 12 reuses were possible without appreciable differences in activity or selectivity1, 5, 41, 42.

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Immobilization of Schiff base metal catalysts on inorganic supports, as with organic supports, has found abundant use. Mesoporous materials—MCM-41, MCM-48, SBA-15, silica, amino-modified silica43-47—and zeolites48-50 have served as supports for a variety of Schiff bases.

Metal complexes of various immobilized ligands (31–35) showed excellent conversions and high selectivity in the epoxidation of cyclic and aryl–linked alkenes with t-BuOOH, H2O2 or O2/t-BuOOH at 60–100 °C. Depending on the type of support, recycling of this type of catalyst is possible without significant diminution in activity or selectivity.

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Metal complexes 36–39 of tridentate Schiff bases have been immobilized on organic-inorganic hybrid supports (ZPS-PVPA, ZCMPS-PVPA) via covalent bonding51-53. Epoxidations carried out at 75 °C with t-BuOOH resulted in almost quantitative conversions and high selectivity. The use of catalysts with aliphatic α,ω-diamine spacers of variable carbon chain lengths showed no significant differences. Attempts to recycle this type of catalyst resulted in only slight decreases in yield and selectivity after up to 12 runs.

2.2 Sulfoxidations

Since most of the published literature regarding the use of phenolate ligands in the catalytic oxidation of sulfides is in the area of asymmetric catalysis, special emphasis will be given to this type of reaction.

Organic sulfoxides and sulfones can be obtained by sulfide oxidation. Sulfoxides constitute a very important class of compounds that can be used as synthetic intermediates for the construction of other molecules. Chiral sulfoxides can be used as synthons. The sulfoxide group has a trigonal pyramidal structure, with an electron pair at the apex; the energy required for the elctron pair to migrate to the axially opposite position is sufficiently high to allow the existence of two stable enantiomers when the S[DOUBLE BOND]O bears two different groups. These compounds are also present in many important therapeutic agents such as Esomeprazole, used in the treatment of gastric and duodenal ulcers, and Armodafinil, a stimulant for the treatment of sleep disorders54.

The catalytic asymmetric oxidation of prochiral sulfides is the most attractive route to obtain optically active sulfoxides55. Since the pioneering work of Kagan56, 57 and Modena58, on the asymmetric oxidation of sulfides with Ti(OPr-i)4/chiral tartarate ligands, the asymmetric oxidation of sulfides catalyzed by chiral metal complexes has been extensively investigated, several reviews having been published on the topic54, 59-61. Among the complexes of metals such as Ti, Mo, Fe, V, W, Re, Ru and Mn which have been used for these reactions, those of titanium(IV) and vanadium(V) are the most widely used. In recent years vanadium complexes have received considerable attention62, 63.

In the enantioselective oxidation of sulfides various types of ligands have been commonly used, such as diols, tridentante {ONO} ligands and tetradentate ligands, especially of the salen type64a. Some of these ligands are phenolates, namely tridentate Schiff bases and salen-type ligands. The latter are discussed elsewhere in the present volume64b.

Different types of oxidants have been used for the metal catalyzed oxidation of sulfides, namely t-butyl hydroperoxide (TBHP), cumyl hydroperoxide (CHP) and urea hydrogen peroxide (UHP), with special emphasis on H2O2, an inexpensive and environmentally benign oxidant65.

Karpyshev and coworkers66 described the use of vanadium complexes of Schiff bases (40a–c) for the oxidation of sulfides with hydrogen peroxide as oxidant. Two methods were used for the addition of the oxidant, fast and stepwise addition. Enantioselectivity of the sulfide oxidation was found to improve by the stepwise addition mode. All ligands showed moderate to high conversions (60–93%) and ee ranging from 27% to 51% (best result with ligand 40c, for the oxidation of phenyl thioether 41b, with stepwise addition of the oxidant, equation 2). The higher chemical and optical yields obtained by stepwise addition of hydrogen peroxide were attributed to the formation of monoperoxo- and a diperoxovanadium complex. The asymmetric oxidation of the sulfides is catalyzed by the chiral monoperoxo complex and, in the presence of excess oxidant (fast addition), the chiral ligand can be substituted by O2 and a diperoxo complex can be formed. The formation of this complex results in a decrease of the optical yield of the products.

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In 1995, Bolm and Bienewald67 reported the use of chiral complexes formed in situ from vanadyl acetylacetonate and chiral Schiff bases 40c, 42a and 42b for the catalytic oxidation of sulfides with H2O2 and as little as 0.01 mol% of catalyst, giving ee up to 85%. This catalytic system has several advantages such as the ease of ligand preparation (from salicylaldehydes and chiral 1,2-aminoalcohols), low catalyst loadings, no need of air exclusion and the use of a safe and inexpensive oxidant68. Since then a great number of studies has been published concerning the use of Schiff base ligands for the catalytic oxidation of sulfides. Ligand 42b and the corresponding enantiomer were also tested in the sulfoxidation of homoallylic sulfides69 with good results (equation 3). The reactions were carried out with H2O2 with the vanadium complex of 42b, in dcm at 0 °C.

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Pelotier and coworkers70, using 1 mol% of vanadium complex of 43 and 27% H2O2 in dcm at 0 °C, obtained very good results in the oxidation of various sulfides, with good yields of sulfoxide (76–85%) and excellent ee values (89–97%). The highest ee was obtained in the oxidation of 2-naphthyl methyl sulfide, 97%. Several authors report the use of halogen functionalized chiral Schiff bases for the asymmetric oxidation of sulfides. This type of ligand shows good ee when compared to analogous Schiff bases with other substituents on the aromatic ring.

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Using 43 and similar ligands, Bolm and Legros71 described for the first time the use of an iron catalyst for the enantioselective oxidation of sulfides. Best results were obtained for the in situ formed iron catalyst. Several aryl methyl sulfides were oxidized with this catalytic system, with low yields (21–44%) and moderate to high ee (59–90%). This system has the advantage of using Fe(acac)3, an inexpensive metal precursor, hydrogen peroxide as the oxidant and the simplest reaction conditions (room temperature and no need for an inert atmosphere). Better yields (up to 78%) and ee (up to 96%) were obtained72, 73 using the same catalytic system and carboxylic acids or their lithium salts as additives. The use of electron-rich benzoic acids, such as p-methoxybenzoic acid or the corresponding Li salt, resulted in the highest ee values.

In an effort to understand the role of the aromatic substituents in the sulfide oxidation, Hinch and coworkers74 prepared a series of Schiff base ligands, structurally analogous to 43, with different substituents on the aromatic ring. Ligands 44 were prepared from (R)-t-leucinol and several 3,5-disubstituted salicylaldehydes. The 3-iodo derivatives showed better enantioselectivities when compared to C3 unsubstituted ligands in the sulfoxidation of thioanisole with 1.2 equiv of H2O2 and 1 mol% of the vanadium complex, in dcm at 0 °C. Good results were obtained with the 3-iodo-5-chloro derivative (83% yield, 88.5% ee) and the 3,5-dichloro derivative (79% yield, 88.0% ee), but best results were obtained with the 3,3-diiodo ligand (75% yield, 92.1% ee).

Gama and coworkers75 created a library of Schiff base ligands (45) derived from salicylaldehydes with subtle variations in the size of the different ligand substituents. The vanadium complexes of these ligands were used in the enantioselective oxidation of thioanisole with H2O2; good results (ee up to 51%) were obtained when R4 and R5 formed a CH2C6H4 bridge, giving an indanyl substructure, and R1 was t-Bu or 1-Ad. Replacing R4–R5 bridge by R4 = t-Bu and R5 = H improved the ee. It seems that some steric crowding is needed, but not in excess, in order to obtain good ee. Therefore, lower ee were obtained when R4 and R5 were both different from hydrogen. The presence of electron-withdrawing bromine at R1 or R2 enhances the enantioselectivity.

Weix and collaborators76 reported the use of a ligand structurally similar to 45, with R4, R5 = cis-1-amino-2-indanyl, R1 = R2 = t-Bu and R3 = H for the oxidation of di-t-butyldisulfide, using hydrogen peroxide and 0.52 mol% of the vanadium complex, in acetone, obtaining a conversion of 98% and an ee of 86%. Scaling-up of the reaction to 1 kg of substrate was possible without affecting either the conversion or the ee. The resulting sulfoxide is a precursor of t-butanesulfinamide, a versatile chiral ammonia equivalent for the synthesis of amines. Khiar and coworker77, employing the same reaction system in the oxidation of several functionalized, sterically hindered disulfides, obtained the corresponding sulfoxides with low to moderate yields and very low ee.

Gao and collaborators78 described the synthesis of several dibromo- and diiodo-functionalized chiral Schiff base ligands 40b, 40c, 43 and 46. These ligands were used for the catalytic oxidation of aryl methyl sulfides, with hydrogen peroxide and 1 mol% vanadium catalyst (equation 4). The effect of additives (4-methoxybenzoic acid and its carboxylate salt) on the catalytic system was also studied. Best results in the oxidation of thioanisole were obtained with 46b and 46c derived from (S)-valinol with two Br or two I atoms on the benzene ring (79 and 84% yield and 81 and 88% ee, respectively), suggesting that the stereoelectronic effect of the substituents on the 3- and 5-positions of the salicylidenyl moiety of the Schiff base ligand plays an important role in the asymmetric induction. An ee of 92% (S) was obtained in the oxidation of p-bromothioanisole with 46c. Additives did not improve the results.

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Liu and coworkers79 synthesized a series of ligands 40b and 47 in order to study the influence of substituents o- to the phenolic hydroxyl group of chiral Schiff bases in the vanadium catalyzed asymmetric oxidation of prochiral sulfides. Optimized reaction conditions (H2O2, 1 mol% catalyst, dcm at 0 °C) were used in order to study the asymmetric oxidation of thioanisole with the various ligands. Introduction of an aryl group in the 3-position of the salicylidenyl moiety improved the enantioselectivity. Higher enantioselectivities were obtained with 47f and 47g, 74 and 77% respectively. Oxidation of other aryl methyl sulfides in the presence of VV47g gave products with yields from 76 to 85% and ee from 73 to 90%, the best results being obtained for 2-naphthyl methyl sulfide.

The first application of carbohydrate-derived auxiliaries in the synthesis of Schiff bases for enantioselective sulfide oxidation was reported by Cucciolito and coworkers80. Several ligands derived from glucose and allose (48–50) were prepared and used in the asymmetric oxidation of thioanisole. Using these complexes and hydrogen peroxide as oxidant, all the reactions were complete after 1 hour, with selectivities for sulfoxide from 85–97%. The ee were modest, with best result being obtained with 48b, 60% (S). Recently81, the use of an oxovanadium(V) complex 51, derived from 6-amino-6-deoxy-1,2,3-tri-O-methyl-α-d-glucopyranoside and 3,5-di-t-butylsalicylaldehyde, was reported. This complex was used in the oxidation of thioanisole and phenyl benzyl sulfide using hydrogen peroxide or t-butyl hydroperoxide in dcm at room temperature. Modest ee were obtained for both oxidation products with hydrogen peroxide (26% and 16%, respectively), while the racemic product was obtained in the oxidation of thioanisole with TBHP.

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Koneva and collaborators82 prepared several Schiff bases derived from (+)-3-carene that were tested in the vanadium-catalyzed oxidation of thioanisole. Although conversions were high, very modest ee were obtained with all the catalysts, the best being 20% ee with 52.

Most of the catalytic systems that use Schiff base ligands for sulfoxidation involve vanadium or iron complexes. Titanium-based systems have been mainly used with diol and tetradentate salen-type ligands65. Bryliakov and coworkers83 reported the use of several titanium complexes of Schiff bases 40 and 46 for the oxidation of sulfides. 40b gave the best results (96% conversion and 60% ee) for the oxidation of phenyl benzyl sulfide at 20 °C, using a ratio of [BnSPh]:[H2O2]:[Ti(OPr-i)4]:[ligand] = 21:19:1:1.5. It was found that variations in temperature (−20 or 0 °C) or oxidant (urea hydroperoxide) did not increase the ee.

Recently, Wang and coworkers84 tested several titanium complexes of Schiff bases (40b, 40c and 53) in the oxidation of aryl methyl sulfides. The reaction conditions were optimized with 53b and using thioanisole as substrate. Best results were obtained with hydrogen peroxide as oxidant, at 0 °C in dcm and a molar ratio of Ti(OPr-i)4: ligand of 1:1.2. Under these conditions, thioanisole was oxidized to the corresponding sulfoxide in 89% yield and 73% ee. With the optimized reaction conditions, the other ligands were used and best yields and ee were obtained with 53 containing cumenyl groups at the 3,5-positions of the salicylidenyl units. 53b was also used in the oxidation of p-bromophenyl methyl sulfide and p-methoxyphenyl methyl sulfide. The sulfoxides were obtained in 84 and 79% yield and 54 and 59% ee, respectively.

In recent years, several Schiff bases have been used with good results for the enantioselective oxidation of sulfides and concomitant kinetic resolution. Zeng and coworkers85 reported the use of the preformed chiral vanadium–Schiff base complexes 54 for this purpose (equation 5). Better ee were obtained with the preformed catalyst than with those prepared in situ. It was suggested that this is due to the incomplete formation of the complexes from the Schiff bases when the H2O2 was added, the residual VO(acac)2 being transformed into [VO(O2) O2 H], which racemically oxidized sulfides. Best results were obtained when R2 = Bn or i-Bu, using 5 mol% catalyst in dcm with H2O2 as oxidant. High ee (85–91%) and good yields (52–65%) were obtained for thioanisole, at 0 °C, when the reaction time was 4 h. Kinetic resolution occurs because VV-Schiff base complexes transform the (R)-sulfoxide into sulfone, leaving the (S)-form unchanged, thus increasing the ee values. For other methyl aryl sulfides, ee values ranging from 81 to 99% were obtained.

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The use of the (R)-enantiomer of 43 for the asymmetric oxidation of sulfides and subsequent kinetic resolution was also reported86. Using 1.2 equiv H2O2 and 1 mol% of VV–[(R)-43] at 0 °C, the kinetic resolution was much more efficient in chloroform than in dcm. Under these reaction conditions thioanisole was oxidized in 70% yield and 96.7% ee. Several alkyl aryl sulfides were also oxidized with excellent ee (86.9–99.5%).

Kelly and coworkers87 observed that using the VV43 complex and p-tolyl benzyl sulfide as substrate, a considerable amount of sulfone was formed during the reaction, but the sulfoxide was obtained with ee >99% (equation 6). This result indicated that kinetic resolution was taking place. A relationship was found between the amount of sulfone formed and the enantiopurity of the sulfoxide and that this was dependent on the amount of oxidant added. Higher ee were obtained using 1.3 equiv of hydrogen peroxide at room temperature. Oxidation of several aryl benzyl sulfides produced sulfoxides with ee ranging from 71 to 99%. Lower ee were obtained for the oxidation of benzyl methyl (10%) and benzyl t-butyl (56%) sulfides. Kinetic resolution also took place using racemic aryl benzyl sulfoxides as substrates, giving the enantioenriched sulfoxides with ee up to 99%.

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Clayden and Turner88 described the oxidative kinetic resolution of racemic sulfinyl-substituted N-alkyl-N, N′-diaryl ureas, using the vanadium complex of 43 (equation 7). A conversion of 50% was obtained with X = t-Bu and R = Me, with the anti diastereoisomer as the major product in good enantiomeric excess. The unreacted reagent was recovered from the reaction medium in 30% yield and an enantiomeric ratio of 97:3.

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Wu and coworkers89 prepared several Schiff base ligands with one or two stereogenic centers (55–58) for enantioselective sulfoxidation. The vanadium complexes of these ligands were used in the oxidation of thioanisole with hydrogen peroxide in dcm at room temperature. Under these conditions, best results were obtained in the presence of 58i, 98% yield and 67% (S) ee of methyl phenyl sulfoxide. The reaction conditions were modified (1.35 equiv of hydrogen peroxide in chloroform at 0 °C), and an ee of 99% was obtained for the oxidation of thioanisole, showing that kinetic resolution was occurring when the oxidant was used in excess. Several other methyl aryl thioethers were also oxidized with excellent ee (98–99%) using 58i.

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Although most of the Schiff bases used in these reactions are of the {NOO} type, there are some references in the literature to the use of Schiff bases of the {NNO} type. Kwiatkowski and collaborators90 reported the use of dioxovanadium(V) complexes (59) of tridentante Schiff bases derived from (R, R)- and (S, S)-1,2-diaminocyclohexane and o-hydroxycarbonyl compounds.

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Thioanisole was oxidized in the presence of 59 using cumene hydroperoxide at 20 and 50 °C. Sulfide conversions were high (>96%) but ee were low (19–23%) for all ligands. When using complexes 60 conversions of 87 to 93% were reached, but again with modest ee (34–39%)91. Later, on Romanowski and Wera92 reported the use of chiral vanadium(V) complexes (61) with tridentate {NNO} Schiff bases derived from (R)-1,2-diaminopropane. Using cumene hydroperoxide or H2O2, thioanisole and phenyl benzyl sulfide were oxidized at room temperature, in high yields (76–97%) but low ee (up to 21%).

Most tridentate ligands used in enantioselective sulfide oxidation are chiral Schiff bases. There are few examples of the use of phenolates, other than Schiff bases, in this type of reaction. Sun and coworkers93 used tridentate {NOO} chiral ligand 62, derived from 8-hydroxytetrahydroquinoline, for this purpose. This ligand was used in the vanadium-catalyzed asymmetric oxidation of aryl methyl sulfides with 1.15 equiv H2O2 and 1 mol% of catalyst in acetone at 0 °C. Thioanisole was oxidized (with dropwise addition of H2O2), giving the sulfoxide with 89% yield and 71% (S) ee. Other aryl methyl sulfides were oxidized with good conversions (80–95%) and ee up to 77% for 2-naphthyl methyl sulfide.

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Although vanadium–chiral Schiff base complexes show enormous potential for the asymmetric oxidation of sulfides, the mechanism of this reaction is not yet well known. Jeong and coworkers94, based on several previous studies95-99, proposed that the active species is the hydroperoxo vanadium complex 63, with an exo-configuration.

Reference was made to the use of phenolate complexes of vanadium, molybdenum, manganese, iron and other metals for the non-asymmetric oxidation of sulfides. Mba and coworkers100, 101 refer to the oxidation of several aryl alkyl sulfides and diakyl sulfides, with hydrogen peroxide, using amine trisphenolate ligands (64) and Ti(OPr-i)4 or VO(OPr-i)3 as catalyst precursors. The sulfoxides were obtained in good yields, with catalyst loadings as low as 0.01% (when R = t-Bu). TONs (turnover numbers) and TOFs (turnover frequencies) up to 8000 and 1700 h−1, respectively, were obtained with TiIV catalysts and up to 9900 and 8000 h−1 with VV catalysts. Barroso and collaborators102 carried out the oxidation of thioanisole with 1.2 equiv of hydrogen peroxide at 0 °C, using as catalyst 1 mol% of VV complexes of 65 in dcm and 66 in acetone. Conversions were 96 and >99%, respectively. For 66, the sulfoxide was racemic.

Molybdenum complexes are widely used catalysts in various oxidation reactions, particularly epoxidations, hydroxylation of alkenes, oxidation of alcohols, etc. In the case of sulfide oxidations, the number of publications that refer the use of molybdenum complexes with phenolate ligands is limited. Plass and Mancka103 described the use of Schiff base 67 in the catalytic oxidation of thioanisole. Using 1.2 equiv of hydrogen peroxide, 1 mol% of catalyst and a mixture of dcm and methanol (7:3), the molybdenum(VI) catalyst performed 100 turnovers within one hour. The dioxomolybdenum(VI) complex 1a104 was used in the catalytic oxidation of several sulfides with urea–hydrogen peroxide (UHP). A 1:1 or 1:5 molar ratio of sulfide:UHP was used for sulfoxide or sulfone formation, respectively. The reaction proceeded under mild conditions using 5 mol% catalyst in methanol, open to air at room temperature. In the presence of 1 equiv of UHP, dialkyl, diaryl and aryl alkyl sulfides were oxidized to the corresponding sulfoxides with high conversions (75–100%) and selectivities (93–100%). With 5 equiv of UHP sulfones were obtained in high conversions (95–100%) and selectivity for the sulfone (97–100%). Rezaeifard and coworkers8 reported the use of dioxomolybdenum(VI) Schiff base complex 1e for the oxidation of sulfides using UHP. High yields of sulfoxide (78–100%) were obtained within 35 min, using a 100:100:1 molar ratio of sulfide/UPH/catalyst.

The manganese(III)–tridentate Schiff base complex 68 has been used by Bagherzadeh and coworkers105 in the oxidation of a number of sulfides. Under the optimized conditions, sulfide:UPH:catalyst:imidazole (1:2:0.05:0.5), several substrates were oxidized under air and at room temperature with high conversions (83–96%) but with moderate selectivities for sulfoxide (41–73%). When using the FeIII -complex (69) of a tridentate Schiff base, high conversions (69–94%) as well as selectivities (88–98%) were obtained for dialkyl, diaryl and aryl alkyl sulfides.

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The use of phenolate ligands immobilized on various supports for the oxidation of sulfides has been described. The advantages of these systems are the easy separation of products and a possible recovery and reuse of ligands. Green and coworkers106 prepared and screened a library of ligands immobilized on Wang resin for the oxidation of alkyl aryl sulfides. Best results were obtained with supported TiIV -70, using hydrogen peroxide. High conversions for several alkyl aryl sulfides (61–100%) and moderate enantioselectivities (45–72%) were obtained. Barbarini and coworkers107, using a vanadium complex of a chiral Schiff base supported on polystyrene (71), promoted the oxidation of several aryl methyl sulfides to the corresponding sulfoxides in good yields (54–80%) and moderate ee (45–57%). Merrifield resin was used as support for the oxovanadium(IV) complex of tridentate Schiff base 72108. A conversion of 92% for thioanisole was obtained with this system, using t-BuOOH as oxidant. The polymer-supported complex was reused three times with almost no loss of catalytic activity. The dioxovanadium(V) complex of ligand 35 was encapsulated in zeolite-Y and used in the catalyzed oxidation of thioanisole. Using hydrogen peroxide in acetonitrile at room temperature, a maximum conversion of 96% and selectivity toward sulfoxide of 97% were obtained.

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2.3 Alcohol Oxidations

The oxidation of primary and secondary alcohols to carbonyl compounds is a fundamental transformation in synthetic organic chemistry. Classical oxidation methods include the use of stoichiometric quantities of inorganic oxidants, high valent iodine compounds, dmso, etc. The need for developing less environmentally polluting methods led to the appearance of new synthetic alternatives for the oxidation of alcohols. Among these, metal-catalyzed methods have been extensively explored especially due to the possibility of using ‘green oxidants’ (molecular oxygen and hydrogen peroxide) in these reactions109-113. Metals such as cobalt, copper, iron, gold, palladium, ruthenium and vanadium, among others, are used for these reactions. A large number of metal-catalyzed systems has been developed for alcohol oxidations, some using phenolates as ligands. The literature refers to the use of various metals, copper, ruthenium, molybdenum, iron and cobalt in phenolate-catalyzed reactions.

Paine and coworkers114 reported the use of mononuclear CuII -73 complex in combination with a strong base, n-Bu4N+−OMe, for the catalytic oxidation of primary alcohols to the corresponding aldehydes. Reactions were carried out in the presence of air, in acetonitrile at room temperature. Turnover numbers of 95 and 27 were determined for benzyl alcohol and cinnamyl alcohol, respectively.

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A CuII complex of 74 was described115 and used in the catalytic oxidation of 3,5-di-t-butylcatechol, in CH3CN saturated with molecular oxygen, at different temperatures (25, 15, 5 and 0 °C). The corresponding o-quinone was obtained with conversions ranging from 98 to 100% after 24 h for all the temperatures.

The oxidation of benzyl alcohol, cinnamyl alcohol and cyclohexanol in air was reported by Manimaran and coworkers116 using CuII complexes with Schiff base ligands 6a and 75. The reactions were carried out with air and N-methylmorpholine N-oxide (NMO) as cooxidant, in dcm at room temperature. Moderate conversions (43–60%) were obtained for the three alcohols with all the Schiff base complexes.

Ahmad and coworkers117 tested a series of CuII complexes (76) with Schiff bases derived from 3,5-di-t-butylsalicylaldehyde and several amines in the catalytic oxidation of benzyl alcohol. Under optimized reaction conditions, 1 atm O2, 1.3 mol% of TEMPO (2,2,6,6-tetramethyl-piperidinyloxyl) as co-catalyst, 0.33 mol% of the complex, in toluene at 60 °C, 76g provided the highest activity in the aerobic oxidation of benzyl alcohol (78% conversion). Complex 76g was also used for the oxidation of several other alcohols. Mono-, di- and trimethoxybenzyl alcohols gave quantitative conversions to the corresponding benzaldehydes in two hours. The presence of electron-withdrawing groups, such as nitro groups, in the substrate, resulted in lower conversions.

Recently, Ramakrishna and coworkers118 reported the use of copper(II)-Schiff base complexes 77 in the oxidation of several primary and secondary benzyl alcohols and alkanols with good to high conversions. Best results were obtained with 77a, using 1 equiv of periodic acid and 1 mol% of the complex in acetonitrile at room temperature. Benzyl alcohols were converted to the aldehydes or ketones with higher yields (90–93%) than alkanols (71–91%).

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Ruthenium complexes of tridentate Schiff bases 5a, 5b and 6a were used in the oxidation of cyclohexanol and benzyl alcohol119 with t-BuOOH. Moderate conversions (48–62%) were obtained with all ligands for both substrates, in dcm at room temperature.

Kumar and collaborators120, 121 refer the use of azophenolates 78 and 79 in the catalytic oxidation of benzyl alcohols and alkanols. A complex of 78 was prepared using [RuHCl(CO)(AsPh3)3] as precursor, and studied in the oxidation of alcohols with molecular oxygen in the presence of NMO as cooxidant using a 1:100 molar ratio of catalyst to substrate. Reactions were carried out in refluxing dcm for 3 hours. Benzaldehyde was obtained in 60% yield. Cinnamyl alcohol was oxidized to cinnamaldehyde with a conversion >93%. Primary alcohols such as 2-phenylethyl alcohol, citronellol and geraniol gave low conversions (19%, 38% and 38%, respectively), requiring longer reaction times. Secondary alcohols such as benzhydrol, 1-phenylethanol, butan-2-ol, 4-methylpenta-2-ol, cyclohexanol were oxidized with excellent conversions (94–99%).

The catalytic performance of the p-cymene ruthenium(II) complex of 79 was evaluated in the oxidation of primary and secondary alcohols in dcm, in the presence of NMO. Benzyl, primary and secondary alcohols were oxidized with high conversions (77–94%), except for benzoin (56% conversion); aliphatic aldehydes and ketones were obtained in good yields (83–97%).

RuIII complexes of Schiff bases 80 with PPh3 or AsPh3 as coligands were used by Sathya and coworkers122 in the oxidation of benzyl alcohol, cyclohexanol, propan-1-ol and isobutyl alcohol. The reactions were carried out with molecular oxygen using 2 mol% of the complexes in dcm at room temperature. Yields of 84%, 82%, 49% and 58% were obtained for benzaldehyde, cyclohexanone, propionaldehyde and isobutyraldehyde, respectively, using one of the Schiff base ligands (R = Ph) and AsPPh3 as coligand.

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Manimaran and coworkers123 reported the use of {NNOO}-type ligands (81) in the selective oxidation of alcohols to carbonyl compounds. Complexes of RuIII81 with triphenylphosphine as coligand were studied in an O2 atmosphere and using MNO and H2O2 as cooxidants at room temperature. Moderate to high conversions were obtained for all substrates and ligands studied. Best results were obtained with RuIII81c, using MNO as cooxidant (conversions 69–92%, for several primary and secondary alcohols).

Ruthenium complexes prepared from the reaction of [RuCl2(PPh3)3] and tridentate {NNO}82a–82e were used in the oxidation of alcohols to carbonyl compounds in ethylmethyl imidazolium chloride [EMIM] ionic liquid media and with NaOCl as cooxidant124. With molecular oxygen and in the absence of the cooxidant, only poor yields (<15%) were obtained in the oxidation of benzyl alcohol. Reactions using 1 mol% of the complexes were complete after 30 min at room temperature. All five complexes showed high activity in the oxidation of several primary and secondary benzyl alcohols and alkanols, the lowest conversions being obtained with 82e (68–83%) and the highest one with 82a (72–95%). The efficiency of the ionic liquid was tested by reuse in the oxidation of benzyl alcohol. Only a slight decrease in the conversion was observed (from 90% to 80%) after seven cycles.

Substituted aromatic alcohols were found to be more reactive, the corresponding ketones being obtained in high yields (90–97%). Substituted aliphatic alcohols were converted to the ketones in moderate yields (40–70%). Ramakrishna and coworkers125 optimized the conditions for benzyl alcohol oxidation with NaOCl, catalyzed by CoII82 complexes and in [EMIM]Cl (1-ethyl-3-methyl-imidazolium chloride) ionic liquid as solvent. Best results were obtained using 2 mol% of the CoII82 complex, 1 equiv of oxidant and a reaction time of 15 min, at room temperature. The catalytic activity of the other ligands was studied and it was observed that the activity decreased with increase in the bulkiness of the substituents, probably due to steric hindrance which can affect the planarity of the ligand in the complex. Both aliphatic and benzyl primary and secondary alcohols were oxidized with high conversions (73–95%), in the presence of CoII82a complex. Ramakrishna and coworkers126 also prepared NiII complexes of the same ligands for the oxidation of several alcohols. In the oxidation of benzyl alcohol with 1 equiv NaOCl, 2 mol% of the complex, EMIM and a reaction time of 15 min at room temperature, moderate to high conversions (69–95.6%) were obtained for aromatic and aliphatic primary and secondary substituted alcohols, similarly to the case of the CoII complexes. Both the ionic liquid and the catalyst were recovered in up to 92% and could be recycled at least 10 times.

Wong and coworkers127 reported the use of several complexes of dioxomolybdenum(VI) and tungsten(VI) with {NNOS} (83) and {NOSS} (84) phenolate ligands for the oxidation of benzoin. Using dmso as oxo-donor at 100 °C, conversions of 75–86% were obtained with dioxomolybdenum complexes and 14–53% for the corresponding tungsten complexes. The authors justified the higher activity and shorter reaction times of molybdenum complexes as resulting from the lower metal-based reduction potentials of these complexes when compared to the tungsten analogues.

Gharah and coworkers128 prepared oxoperoxomolybdenum(VI) and tungsten(VI) complexes of 17b. Using hydrogen peroxide and 1 mol% of the complexes in refluxing acetonitrile, several alcohols were oxidized to the corresponding carbonyl compounds. The tungsten complex showed slightly better conversions (65–99%) than the molybdenum ones (63–98%) with all substrates used. For almost all primary aliphatic alcohols, the formation of acid was observed in moderate percentages with both catalysts.

CoII complexes 85–87 were used in the aerobic oxidation of secondary alcohols using 5 mol% of catalyst in acetonitrile at room temperature129. All the complexes catalyzed the oxidation of 4,4′-dimethylbenzoin with complete conversion, with 85 showing the shortest reaction time (0.75 h). This complex was used in the oxidation of other secondary alcohols giving moderate to excellent conversions.

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FeIII complexes of 88 were synthesized130 and used to oxidize alkanols and benzyl alcohols with H5IO6. In the oxidation of benzyl alcohol with 4 mol% of catalyst, in acetonitrile at 70 °C, conversions of 81–86% were obtained with all the complexes. The reaction was extended to a variety of primary and secondary alcohols with aromatic and aliphatic substituents. While alcohols containing aromatic substituents were more reactive than the aliphatic ones, moderate to high conversions were obtained with all complexes (42–86%).

Vanadium complex 89 with cathecol ligands131 was used in the oxidation of benzyl alcohol, cyclohexanol and 1-phenylethanol, with t-butyl hydroperoxide in toluene. Yields of 71%, 64% and 74% were obtained for benzaldehyde, cyclohexanone and acetophenone, respectively. When the solvent was acetonitrile, benzyl alcohol was oxidized to benzoic acid (70% yield) and benzaldehyde (30% yield). Cyclohexanone and acetophenone were obtained in 82% and 86% yield, respectively.

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Many homogeneous metal-catalyzed systems have been developed for the oxidation of alcohols. Heterogeneous catalysts are less studied due to their lower activity when compared to homogeneous systems132. Recently, Gupta and coworkers133 published a review on polymer-supported Schiff base complexes in oxidation reactions using immobilized systems for alcohol oxidations with good results. References are made to some systems that use phenolate ligands in the oxidation of alcohols.

A RuIII–Schiff base complex was immobilized on a chloromethylated styrene–divinylbenzene copolymer (90) and used in the oxidation of benzyl alcohol134. The polymer-bound catalyst proved to be more efficient than its homogeneous counterpart135. Shen and coworkers136 reported the use of a similar system (91) for the oxidation of eight substrates (substituted aromatic and aliphatic alcohols). In the presence of 0.0034 mol% of polymer-supported Ru-catalyst, with molecular oxygen at 35 °C in methanol, all the alcohols studied showed good conversions (65–89%). The catalytic system was recycled 10 times using cinnamyl alcohol as substrate, and no significant decrease in the catalytic activity was observed (from 88% to 86% conversion).

Jain and Reiser137 immobilized several cobalt Schiff base complexes on polystyrene resins and the catalytic efficiency of these catalysts (92–96) was evaluated and compared with their homogeneous analogues. Alcohols were oxidized with molecular oxygen using 2 mol% of the complexes and 2-methylpropanal as reducing agent in acetonitrile at 50 °C. With benzhydrol as substrate results showed that immobilized complexes were more active than the free analogues. The polymer-supported catalysts were recycled 5 times with no decrease in yields of formation of benzophenone (96–98%). A variety of primary and secondary alcohols were oxidized with high conversions (90–98%) in the presence of all of the immobilized systems.

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Islam and coworkers138 described the immobilization of a Co(II)–Schiff base complex on amino-polystyrene (97). In the oxidation of benzyl alcohol with t-butyl hydroperoxide, in acetonitrile at 50 °C, benzaldehyde and benzoic acid were obtained in 70% and 30% yield, respectively. Three cycles of recycling showed almost the same catalytic activity.

Besides polymers, several other materials have been used for preparing supported catalysts. One of the most common is mesoporous silica. A CoII–Schiff base complex was grafted on mesoporous silica (32b) and used in the oxidation of several alcohols139. Reactions were carried out in an oxygen atmosphere, using 0.25 mol% (cobalt content) of the immobilized complex and 10 mol% of N-hydroxyphthalimide in MeCN at 60 °C. Secondary alcohols were oxidized to the corresponding ketones with high yields (88–100%) and primary alcohols were also oxidized with good yields (79–89%) to carboxylic acids. Five consecutive runs of oxidizing 1-phenylethanol gave acetophenone in almost quantitative yields.

2.4 Alkane Oxidations

Nowadays 90% of the existing organic chemicals are derived from petroleum, the main components of which are hydrocarbons. Oxidation of these hydrocarbons allows the synthesis of oxygenated compounds (alcohols, ketones, carboxylic acids) which are important intermediates in organic synthesis. Traditionally, hydrocarbons were oxidized with inorganic agents such as nitric acid, chromium and manganese oxides, among others140. In recent decades the oxidation of hydrocarbons catalyzed by transition metals has been the object of innumerable publications, some of which concern the use of phenolate–metal complexes as catalysts.

RuIII complexes of ligands 5 and 6 were used with t-BuOOH in the oxidation of cyclohexane to yield cyclohexanol (≤10%) and cyclohexanone (≤30%) and toluene to yield benzyl alcohol (≤8%) and benzaldehyde (≤37%)119.

Tong and coworkers141 described the use of the cobalt complex of the chitosan–Schiff base 98 in the oxidation of cyclohexane with O2. Optimized reaction conditions, oxygen pressure of 1.6 MPa, at 145 °C and a reaction time of 4.5 h led to a conversion of 10.6% and a selectivity of 84% of cyclohexanone. The catalyst was reused three times with decrease in conversion (9.6, 8.1 and 7.6%).

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Godbole and coworkers142 used iron complexes with 2-(2-hydroxyphenyl)oxazoline derivatives (99) in the oxidation of toluene, ethylbenzene and cumene with hydrogen peroxide, using a substrate:H2O2:catalyst molar ratio of 1000:100:1. Conversions up to 19.8% were obtained, the major products being the corresponding α-OH alcohols in all cases.

An iron complex of ligand 100 was used in the oxidation of cyclohexane and n-heptane with hydrogen peroxide in acetonitrile143. The reactions were performed at 50 °C and a substrate:oxidant:catalyst ratio of 100:150:1 was used. For cyclohexane, a conversion of 100% was achieved with 51% yield of cyclohexanone and 39.5% cyclohexanol as the major products. The observed conversion for n-heptane was 38%, yielding a complex mixture of products alcohols, ketones and aldehydes.

Roy and Manassero144 used tetranuclear copper complexes of Schiff bases 101 for the oxidation of cyclohexane and toluene with hydrogen peroxide in the presence of nitric acid. Best results were obtained with 101(X = Br), after 48 h, using a molar ratio of H2O2: catalyst of 500, at ambient temperature. Conversions of 38.2% and 42.4% were observed for cyclohexane and toluene, respectively.

Some reference is made in the literature to the immobilization of phenolate complexes for the catalytic oxidation of alkanes. Mirkhani and collaborators145 refer to the use of Schiff base complexes covalently anchored on polyoxometalate (POM) (102) in the oxidation of several alkanes with hydrogen peroxide, using 2 mol% of the catalysts in acetonitrile at 80 °C. The influence of the metal center was studied in the oxidation of cyclooctane and the most active catalyst was found to be the iron complex, with 57% conversion after 5 h (3% of the alcohol and 54% of the ketone). This complex was then used in the oxidation of various other substrates with conversions up to 70%, the major products being ketones (selectivities up to 100%), except for adamantane, where the main product was the alcohol (94% and 6% of ketone).

Maurya and coworkers146 prepared polymer-supported complexes of amino acid tridentate ligands (103) for the oxidation of p-chlorotoluene with hydrogen peroxide in acetonitrile at 80 °C. The polymer support, chloromethylated polystyrene crosslinked with 5% divinylbenzene, was reacted first with 3-formylsalicylic acid and then with alanine or isoleucine. Complexes of vanadium and copper were prepared with the free and polymer-bound ligand, all leading to low conversions (7–13.8%) and mixtures of several products.

2.5 Diverse Oxidation Processes

There are references in the literature to the use of phenolate ligands for a variety of metal-catalyzed oxidations, such as oxidative halogenation147-149, amine oxidation114, oxidation of phenol and phenol derivatives150, 151, ascorbic acid oxidation152, asymmetric oxidation of α-hydroxy esters and amides153-155 and other oxidative processes156, 157, that will not be discussed in detail for lack of sufficient information.

3 Additions to Carbonyl and Imine Groups

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References

3.1 Cyanation Reactions

Cyanation of aldehydes, ketones and imines constitutes one of the fundamental carbon-carbon bond-forming reactions in organic synthesis158. The asymmetric version of these reactions is of particular interest since chiral cyanohydrins and aminonitriles are precursors of other important compounds, namely α-hydroxy acids, α-hydroxy ketones, primary and secondary β-hydroxy amines, α-hydroxy esters and α-amino acids, among others159, 160. These compounds are widely used as chiral building blocks in pharmaceuticals and agrochemicals.

One of the methods used for the synthesis of cyanohydrins and aminonitriles involves the addition of cyanide to carbonyl compounds or imines, catalyzed by a metal complex. Several metals (Al, Ti, V, etc.) and types of ligands (diols, Schiff bases, amino alcohols, sulfoximines, etc.) are used in these reactions. Different sources of cyanide can be used, namely hydrogen cyanide, sodium or potassium cyanide, acetone cyanohydrin, acyl cyanides, cyanoformates, etc. The most commonly used cyanide source is trimethylsilyl cyanide (TMSCN), which originates O-trimethylsilyl products.

The existing literature concerning the enantioselective synthesis of cyanohydrins is quite extensive and has been the object of several recent reviews158-162. Since Oguni's initial studies163-165 many phenolate ligands (especially tridentate and tetradentate Schiff bases) have been used and found to be very efficient in the enantioselective trimethylsilylcyanation of aldehydes and ketones (equation 8).

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Based on Oguni's164, 165 and Jiang's166, 167 studies, Flores-López and coworkers168, 169 reported the use of several Schiff base ligands (104a–k), derived from cis-1-amino-2-indanol, for the asymmetric addition of trimethylsilyl cyanide to benzaldehyde in the presence of titanium tetraisopropoxide. Using 20 mol% of catalyst in dcm at −78 °C, ligand 104e proved to be the most efficient in the enantioselective cyanation of benzaldehyde, cyanated product being obtained in 64% yield and 85% ee. This ligand was also used in the asymmetric cyanation of several aromatic aldehydes with yields and ee ranging from 48 to 77% and 21 to 95%, respectively. The best results were obtained for 4-methoxybenzaldehyde with 77% yield and 95% ee. When using Schiff base ligands 105a–i169 under the same reaction conditions in the enatioselective cyanation of benzaldehyde, moderate yields (15–60%) and ee (12–68%) were obtained. Later on a library of structurally similar ligands was prepared with different R substituents (106, 106′), which were used in the presence of Ti(OPr-i)4 for the cyanation of benzaldehyde with TMSCN, with moderate to good yields (16–85%)170. Ligand 106 of (S) configuration, with R1 = t-Bu, R2 = H, R3 = i-Pr, R4 = R5 = H, gave an ee of 85%. It was concluded that increasing the number of stereogenic centers around the metal is not essential for obtaining good enantioselectivity and that the type of R3 substituent affects the ee of the product. Belokon and colleagues171 reported the use of Ti complexes of {ONO}-tridentate Schiff bases 40b and 46a in the addition of TMSCN to benzaldehyde, with quantitative yields of mandelonitrile trimethylsilyl ether (ee 46% (S) and 19% (R)), when using 20 mol% of catalyst in dcm. Reversal of the product configuration was observed with the introduction of bulky substituents in the salicylaldehyde moiety of the ligands.

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Yoshinaga and Nagata172 used partially hydrolyzed titanium alkoxide (PHTA) and Schiff base 40b for the enantioselective silylcyanation of aldehydes and ketones. Higher ee were obtained when Ti(OBu-n)4 was used and when it was hydrolyzed with one equivalent of water. A conversion >99% and an ee of 87% were obtained for heptanal with 0.2 mol% of catalyst. Secondary aliphatic aldehydes such as cyclohexanecarbaldehyde and 2-ethylbutyraldehyde gave excellent ee (97% in both cases). Aromatic aldehydes showed ee ranging from 89 to 92% and acetophenone and cyclohexylmethylketone afforded the corresponding products with 88% and 90% ee, respectively.

Moreno and coworkers173 prepared several Schiff base ligands derived from 2-amino-2-ferrocenylethanol (107) for the enantioselective cyanation of aldehydes with TMSCN in the presence of Ti(OPr-i)4; best results (91% yield and 86% ee) were obtained with 107f and benzaldehyde as substrate. Ligand 107d was reduced to the corresponding amine and used in the cyanation of benzaldehyde; however, a poor ee (16%) was obtained when compared to that of the corresponding Schiff base (70%). Moderate results (47–85% yield and 14–64% ee) were obtained when 107d and 107e were used in the cyanation of several aromatic and two α,β-unsaturated aldehydes.

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Rodríguez and colleagues174 reported the use of several Schiff base ligands (108–110) for the cyanation of aldehydes with TMSCN. While 110 exhibited modest yields (up to 58%) and ee (up to 64%), better results were obtained with ligands derived from (2S, 3S)-phenylglycidol, 108 and 109. Results show that conversion and enantioselectivity decrease as the bulkiness of the OR group increases. Ligand 109 (R = Me) was the most efficient one, affording 87% conversion and 75% ee for benzaldehdye at −40 °C. This ligand was used in the trimethylsilylcyanation of other aldehydes in the presence of titanium isopropoxide with good results. Aromatic aldehydes gave high conversions (87–100%) and ee up to 77% for o-chlorobenzaldehyde. Two aldehydes with the carbonyl group attached to an alkyl residue were investigated: phenylacetaldehyde showed 67% ee and pivalaldehyde only 28% ee.

Jaworska and coworkers175 prepared several Ti complexes of Schiff bases derived from α-pinene (111a–f) and used them in the enantioselective cyanation of aldehydes with TMSCN. Ligands with bulky substituents on the aromatic ring, such as t-butyl, led to higher ee. Ligand 111c was used in the cyanation of several aromatic and aliphatic aldehydes, giving products with moderate ee (42–80%), except for cinnamaldehyde that presented an ee of 99%.

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The N-sulfonylated-β-amino alcohols 112176 were used in the asymmetric addition of TMSCN to several aldehydes in the presence of Ti(OPr-i)4. Benzaldehyde with 10 mol% of titanium complex of 112a and powdered molecular sieves, in dcm at −65 °C, gave mandelonitrile trimethylsilylether in 100% yield and 96% ee. Other aromatic aldehydes afforded the corresponding cyanohydrins in excellent yields (93–100%) and ee (77–96%), isobutyraldehyde gave 95% ee and cinnamaldehyde 93% ee.

Li and coworkers177 reported the use of titanium complexes of β-amino alcohols bearing a phenolate moiety (113) in the cyanosilylation of aldehydes with TMSCN. Steric and electronic effects of the ligands were examined on the enantioselectivity of the process for benzaldehyde in the presence of Ti(OPr-i)4 as Lewis acid at −20 °C. The highest enantioselectivity (85%) was obtained with 113b; bulkier R1 substituents gave poor ee; furthermore, neither electron-donating nor electron-withdrawing R2 groups increased the ee. Using optimized reaction conditions, several aromatic and aliphatic aldehydes were cyanosilylated in high yields (94–99%); aromatic aldehydes showed better ee (76–94%) than aliphatic aldehydes (57–72%). Ligands 114, with only one stereocenter, gave lower ee (6–12%) than ligands 113 with two stereocenters.

Rowlands178 prepared several ligands containing chiral oxazoline and sulfoxide moieties (115) for the enantioselective cyanation of aldehydes. The Ti complex of the 115b phenolate anion proved to be the best catalytic system. An ee of 60% was obtained in the cyanation of benzaldehyde when a stoichiometric amount of the complex was used. When a catalyst loading of 9 mol% was used, the ee dropped to 54%. Moderate ee resulted in the asymmetric cyanation of other aldehydes (10–61%).

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Belokon and coworkers179 reported the use of CoIII complexes of 116 for the asymmetric trimethylsilylcyanation of benzaldehyde. Several countercations (Na+, H+, K+, Li+, Cs+ and NBu4+) were used and the corresponding complexes were studied. Best results (80% yield and 77% ee) were obtained with the Δ-complex, with K+ as countercation in the presence of triphenylphosphine as co-catalyst. The same authors180 later reported the use of CoIII complexes of 117 for cyanation reactions; Δ(S, S) and Λ(S, S)-complexes were studied using Li+ and Na+ as contercations. An ee of 60% was obtained in the cyanation of benzaldehyde, using 2 mol% of the Λ-117d lithium complex at −20 °C. On addition of TMSCN to other aldehydes and to acetophenone, the same catalyst gave products with modest enantioselectivity (27–42%).

Besides nitrogen- and oxygen-containing phenolate ligands, there is also mention in the literature of phenolate ligands containing phosphorus that have been used in the cyanation of carbonyl compounds. Yang and coworkers181 reported the trimethylsilylcyanation of benzaldehyde and o-methoxybenzaldehyde, catalyzed by titanium complexes of o-hydroxylarylphosphonodiamine ligands (118, 40 mol%) at 0 °C, with good yields (90–98%) and modest ee (21–43%).

Shibasaki and colleagues prepared several phenolate ligands (119) with a phosphine oxide moiety; 119a was used in the cyanation of several aromatic and aliphatic ketones182 with very good results. The effect of the metal precursor was evaluated and Ti(OPr-i)4 proved to be the best for the cyanation of acetophenone (85% yield and 92% ee) using 10 mol% of ligand in thf at −30 °C. Aromatic ketones were cyanosilylated with excellent ee (90–95%). Aliphatic ketones also showed good results, for example, cyclohexyl methyl ketone (90% ee), 4-phenylbutan-2-one (85% ee) and pentyl methyl ketone (76% ee). The same authors183, using 119b, containing a benzoyl substituent on the cathecol moiety, obtained an ee of 97% in the cyanosilylation of acetophenone using 10 mol% of the titanium complex. Reducing the catalyst loading to 2.5 mol% affected neither the yield nor the ee of the reaction. Very good results (82–93%) were obtained with this catalytic system for the silylcyanation of various aromatic and aliphatic ketones. With 119a and changing the metal from titanium to samarium or gadolinium184 it was possible to reverse the configuration of the cyanosilylation products with very good results (62 to 97% ee, with the Ga complex) for aliphatic and aromatic ketones. The Sm complex of 119a (5 mol%) was used in the enantioselective synthesis of a key intermediate (98% yield and 84% ee) of (S)-camptothecin, a promising anti-cancer agent (equation 9). In order to improve the catalytic efficiency of the enantioselective silylcyanation of the key intermediate of (S)-camptothecin, 119b–e were prepared and tested in this reaction185. Best results (100% yield, 91% ee) were obtained with 5 mol% of Sm complex of ligand 119d, bearing two electron-withdrawing F groups on the catechol moiety.

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An important intermediate in the synthesis of oxybutynin (c-HexPhC(OH)CO2CH2 C[TRIPLE BOND]CCH2NEt2, a receptor antagonist for the treatment of urinary diseases) can be obtained by the enantioselective silylcyanation of cyclohexyl phenyl ketone, as was effectively done (100% yield, 94% ee) by Shibasaki and colleagues186, using 1 mol% of the Gd complex with 119a. On raising the catalyst concentration to 5 mol% of this complex, several other aryl cycloalkyl ketones were cyanosilylated in very good yields (97–99%) and ee (82–97%).

Recently, Shibasaki and colleagues187 used ligands 120a–e, structurally analogous to 119 but without a phosphine oxide moiety, for the conjugate addition of cyanide to β,β-disubstituted α,β-unsaturated carbonyl compounds, using TBSCN as the cyanide source. The Sr complex of ligand 120d in 0.5 mol% concentration proved to be the most active catalyst for the cyanation of several aromatic and aliphatic substituted substrates (74–100 yield, 89–99% ee).

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Li and coworkers188 designed a series of proline-based N, N′-dioxide ligands 121 for the asymmetric cyanosilylation of ketones in the presence of titanium. The catalytic activity of the ligands was screened, Ti–121e being the most active. This complex catalyzed the enantioselective addition of TMSCN to acetophenone in 92% yield and 86% ee in the presence of 122 as additive. The scope of the reaction was investigated for several aromatic and aliphatic methyl ketones with good results (62–91% yield and 79–92% ee). More recently, the same research group189 prepared several structurally similar ligands (123) that were used in the enantioselective cyanation of ketones in the presence of N-oxide additives (124). Under optimized reaction conditions (using an equal amount of ligand and additive) acetophenone was treated with TMSCN to give the corresponding product in 96% yield and 90% ee. This system proved to be of general application for a wide range of ketones, both aromatic and aliphatic, giving products with yields and ee ranging from 78–96% and 62–96%, respectively.

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The cyanation of imines is a very versatile method for the synthesis of α-amino acids and derivatives. The first synthesis of an α-amino acid, alanine, was reported by Strecker in 1850, by hydrolysis of a mixture of acetaldehyde, aqueous solution of ammonia and hydrogen cyanide190. Although this reaction has been used since then for the synthesis of racemic α-amino acids191, the development of efficient enantioselective catalytic methods for the asymmetric version of this transformation is much more recent192-194. Sigman and Jacobsen195, using a chiral Al-salen complex, reported the first example of a metal catalyzed enantioselective Strecker-type reaction.

Several complexes have been used for the Strecker reaction, especially aluminum, titanium, zirconium and lanthanide complexes with salen- and binolate-type ligands; however, there are also references to the use of tridentate Schiff bases and other phenolate ligands194, 196. Josephsohn and coworkers197 prepared several peptidic Schiff bases and used them in the titanium-catalyzed cyanation of imines. In the trimethylsilylcyanation of 125 with 10 mol% of Ti complex of ligands 126a–e, products 127 with ee from 10 to 95% were obtained (equation 10). The best result, 85% conversion and 95% ee, was obtained with the TiIV126a complex as catalyst. It was concluded that these peptidic Schiff bases act as bifuncional catalysts and that the R moiety crucially influences reaction efficiency and selectivity.

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Vilaivan and coworkers prepared several titanium complexes of N-salicyl-β-aminoalcohol ligands (128a–j, 128′) for the enantioselective cyanation of imines with TMSCN. In a first paper198 the authors reported the use of 128a–f and 128j and also of the imines structurally analogous to 128a and 128c in the cyanation of N-benzylidenobenzylimine. The β-aminoalcohol ligands showed better results than the corresponding imines and ligands with bulkier substituents on the chiral β-aminoalcohol moiety presented higher enantioselectivities. Ligand 128d, with a t-Bu group, gave the α-aminonitrile in 98% yield and 86% ee. The reaction was extended to other substrates and in all cases the α-aminonitriles were obtained in very good yields (84–99%) and moderate to good ee (44–81%). In subsequent studies, with ligands 128 and 128′199, ligand 128h containing an R1 = s-Bu substituent proved to be as active as 128d.

Ligand (S)-128a was used to study the effect of substrate structure on the enantioselective Strecker reaction. Several N-benzylaldimines were used as substrate and the corresponding chiral α-aminonitriles were obtained in very good yields (93–99%) and moderate ee (51–79%). When N-benzhydrylaldimines were used as substrate, excellent ee were obtained (90–98%). t-Butylbenzhydrylimine and cinnamylbenzhydrylimine gave a modest ee with (S)-128a, but a much higher one with 128h (51% and 91% ee, respectively)199. The effect of protic additives was also studied and the addition of an equivalent amount of propan-2-ol in relation to the complex seems beneficial when the reaction is scaled up.

Several N-benzhydrylbenzaldimine substrates (129) were tested for the synthesis of optically active arylglycinonitriles200, using the Ti complex of ligand (S)-128a (2.5 mol%) with propan-2-ol as additive (equation 11). Excellent ee (91–98%) were obtained in all cases. The optically α-aminonitriles 130 were hydrolyzed to the corresponding α-arylglycines using a 1:1 mixture of HCl/TFA.

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Recently, Seayad and coworkers201 reported the use of partially hydrolyzed titanium alkoxide (PHTA, Ti(OBu-n)4) in combination with (S)-128a,128c,128d,128h and 131a–f for the enantioselective Strecker reaction at room temperature. Using the best catalytic system, the PHTA-128d complex, and n-butanol as additive, N-benzhydrylbenzylimine and other benzyl, benzydryl and N-Boc imines were cyanated to the corresponding α-aminonitriles in very high yields and ee up to 98%. This catalytic system was also used for the asymmetric Strecker reaction of several imines using a mixture of TMSCN and HCN202. Benzyl-protected imines gave ee ranging from 83–91% and benzhydryl-protected imines, 79–98% ee.

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Shibasaki and coworkers203 used Gd-119a and Gd-119d complexes for the enantioselective Strecker reaction of ketoimines. Reaction conditions were optimized and Gd-119d showed better results with N-diphenylphosphinoylimines than with N-benzylimines as substrates. The scope of the catalytic system was investigated and higher ee were obtained with aryl methyl ketoimines (89–95% ee) than with alkyl alkyl ketoimines (51–89% ee). α, β-Unsaturated ketoimines were also used as substrates, giving products with 83–90% ee. The improvement of this catalytic system by using 2,6-dimethylphenol (2,6-XylOH) as additive was also reported204. With this new method, the substrate scope was extended and the catalyst turnover frequency and as well as the ee were enhanced. When substrates 132, 132′ and 132′′ were used, the corresponding α-aminonitriles 133, 133′ and 133′′ (equations 12, 12′ and 12′′) were obtained in excellent yields (>90%) and ee (69–99%). The aromatic and heteroaromatic ketoimines, among 132 and 132′, yielded products with ee of 95–99% and with bicycloalkyl ketoimines 132′′, products with 97–98% ee. The use of HCN as the cyanide source, with a catalytic amount of TMSCN, allowed the reduction of the catalyst amount to 0.1 mol% while maintaining high enatioselectivities (93–99%)205.

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The total synthesis (equation 13) of lactacystin, a natural proteasome inhibitor, involves cyanation of ketoimine 134 with TMSCN, catalyzed by a Gd–119d complex, to yield the chiral α-amino nitrile intermediate 135 (99% yield, 98% ee)206.

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3.2 Alkylations, Alkenylations and Alkynylations with Organozinc Reagents

The enantioselective additions of diorganozinc reagents to aldehydes and imines are versatile and extremely useful synthetic procedures (Scheme 1). From the addition of dialkylzincs, more commonly diethylzinc to aldehydes, optically active secondary alcohols are obtained, while imines yield optically active amines. On the other hand, the addition of alkynylzincs and alkenylzincs to aldehydes gives propargylic and allylic alcohols, respectively. Besides creating a new chiral center from the carbonyl or imine carbon, the reactions allow for the elongation of the carbon chain in the product relatively to the parent substrate and, in the case of alkynylation and alkenylation, for the introduction of an additional functionality. The resulting optically active compounds are of great importance in the synthesis of natural products, pharmaceuticals, agrochemicals and perfumes, in addition to other industrially important basic and fine chemicals207-211.

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Scheme 1. Addition of organozinc reagents to aldehydes and imines

Reactions with diethylzinc require the presence of a coordinating ligand which activates the diethylzinc, allowing it to react with the C[DOUBLE BOND]O or C[DOUBLE BOND]N bond. Many types of ligands have been used for this purpose, namely diamines and their derivatives, diols and amino alcohols, salens, salans and Schiff bases207, 208, 212, some of which are discussed elsewhere in this book64b.

Included in the scope of this chapter on metal phenolates are the hydroxyl-substituted [2.2]paracyclophane derivatives (Rp)-136 and (Sp)-136, which have been used as ligands in these reactions. These are chiral molecules with planar chirality. The presence of substituents with one or more chiral atoms confers additional elements of central chirality. The existence of cooperative effects between the two sources of chirality makes it possible to fine-tune these ligands in order to maximize chiral induction.

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Schiff bases with [2.2]paracyclophane backbones and their reduced counterparts, which are {NO}-type bidentate ligands213-216, have been used in the alkylation of aldehydes with diethylzinc. Using benzaldehyde as substrate with 1–2 mol% ligand, in toluene at room temperature, gave rise to 2-phenylpropanol with excellent conversions214, 215, 217-219. Of the various ligands tested, the (Sp,S) diastereoisomers of 137k and 137l gave products with the highest enantiomeric excess, 90% ee. (Rp,S)-137k gave the same ee, while (Rp,S)-137l provided the chiral alcohol in only 79% ee. For nearly all of the reactions, the (Sp,S) ligands yielded alcohols of (R)-absolute configuration, while the (Rp,S) diastereoisomers gave alcohols of (S)-absolute configuration. Consequently, the [2.2]paracyclophane backbone is responsible for the configuration of the product. It was generally observed that with the Schiff bases where R2 = Me both diastereoisomers showed quite similar selectivity, whereas when R2 = Ph the (Sp,S) ligand was more selective. This is indicative of a cooperative effect of both sources of chirality present in the ligand.

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When Dahmen and coworkers217 used aliphatic and α-branched aliphatic aldehydes as substrates with 137a and 137b, reaction products with ee > 90% were obtained, a very surprising result since these are usually considered poor substrates for most catalysts.

Introduction of bromine atoms in the 137a and 137b [2.2]paracyclophane ligands by Vorontsova and collaborators215, to give 137c and 137d, resulted in reactions with excellent conversions and enantioselectivites, with 137c showing overall higher selectivity than the non-brominated counterparts.

Lauterwasser and coworkers220 used 137k and 137l, which showed the best activity and selectivity for the alkenylation of aldehydes by diethylzinc addition. The active alkyl-alkenylzinc species was generated from 1-octyne via transmetalation, following the modified Oppolzer protocol introduced by Dahmen221. Subsequent reaction using 2 mol% of the ligands at −30 °C with benzaldehyde, as well as with linear, branched, α,β-unsaturated and α-substituted aliphatic aldehydes, resulted in moderate yields and ee up to 95% in the case of the α-substituted aldehydes. Comparing the two diastereoisomers of each ligand, only slight differences in yield and no significant differences in selectivity were observed. On the other hand, in the reactions of heteroatom-substituted alkynes with benzaldehyde, unsatisfactory yields and ee resulted, even when the ligand loading was increased to 5 mol%.

Ligands 137a and 137b were tested in the alkenylation of benzaldehyde with 2 mol% ligand at −30 °C214, 218, 220, 221, with good conversions (≤71%) and ee (≤86%), the more hindered 137a giving the highest values. Substituted aromatic aldehydes gave products with higher ee (≤97%) than the parent benzaldehyde, while aliphatic and α-branched aliphatic aldehydes gave products with ee ≥98%.

As in the alkylation reactions, the chirality of the alkenylation products is determined by the planar chirality of the ligand used. In the presence of 137a,137b,137k and 137l, no formation of the secondary ethylation product, 2-phenylpropanol, was observed.

The catalytic ability of 137a and 137b was additionally explored in the alkynylation of aldehydes with phenylacetylene in the presence of diethylzinc222, 223. The alkynylzinc species, PhC[TRIPLE BOND]CZnEt, was prepared in situ, from the deprotonation of phenylacetylene by diethylzinc in the presence of 5 mol% of ligand and 1 mol% of MeOPEG (polyethylene glycol monomethyl ether, MW 2000) as additive. This additive catalyzes the formation of the alkynylzinc species. Subsequent addition of benzaldehyde gave after 1 h 50% of the alkynylated product with 91% ee, the remaining substrate being transformed to the ethylated product. This was attributed to the greater reactivity of the alkyl vs. alkynyl transfer from the zinc species. When diethylzinc was replaced by the less reactive dimethylzinc, 90% of the alkynylated product was obtained with an ee of 91%. Higher ee was attained for substituted benzaldehydes, e.g. ee as high as 98% for 2-bromobenzaldehyde.

Although analogous to the addition to carbonyl groups, reactions with imines (equation 14) have been less extensively explored, mainly due to their lower activity, requiring the previous introduction and subsequent removal of an activating group (PG). The most commonly used groups for this purpose are N-diphenylphosphinoyl (N-DPP), N-sulfonyl, N-acyl and N-formyl211.

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Both diastereoisomers of 137a and 137b were used as chiral ligand catalysts (L*) for the alkylation of N-acetyl and N-formyl-activated benzylimine216. Reactions were initially carried out in the presence of 1 mol% of ligand and diethylzinc in hexane at 10 °C. Conversions were above 90% for all four ligands tested and ee were above 92%, except for (Sp,S)-137b, 61% ee. The product with the highest ee was obtained with (Rp,S)-137b, 95%. Changing the reaction temperature to 20 °C greatly reduced the reaction time, with only a 2% decrease in product ee. Various substituted benzylimines were subsequently tested with (Rp,S)-137b at 20 °C in order to determine the scope of the reaction. Both electron-rich and electron-poor substrates gave comparably high ee (90–95%) and the selectivity was not influenced by the presence of o- and p-substituents. In contrast to the {NO}-bidentate Schiff bases 137, some of their reduced derivatives, {NO}-bidentate amino alcohols (138) tested by Bräse, were much less efficient in alkylations with diethylzinc218. Using benzaldehyde as the substrate, lower conversions were observed using 10 mol% of ligand in toluene at 25 °C. The overall ee of the products were very modest, 7–26%, with the exception of 138c and 138e, leading to products with ee of 77% and 69%, respectively. These results indicate that introduction of an additional chiral center in these ligands, as is the case of 138d,138e and 138g, does not improve the selectivity. A factor seemingly influencing selectivity is the size of the nitrogen substituents R1, R2 and R3. The ee for the alkylation products obtained in the presence of 138c, 138f and 138h were 77%, 14% and 9%, respectively, the most hindered 138c being the most selective.

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[2.2]Parcyclophane backbone Schiff bases 139 are {NNO}-type tridentate ligands, having an additional coordinating amino group224. Alkylations carried out by Danilova and coworkers in the presence of these ligands proceeded smoothly, with good conversions, 87–89%, giving products with modest ee; the highest one, 65%, was obtained with (Rp)-139d, where a cooperative effect between planar and central chirality seems to be operating. There is, however, no apparent advantage in the presence of the additional coordinating group.

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[2.2]Parcyclophane-derived Schiff bases 140 are also tridentate ligands, but with an additional hydroxyl coordinating group225. Alkylations using these ligands progressed with quantitative conversions in almost all cases. The most selective ligands were (Sp,S)-140a and (Sp,S)-140b, both with planar and central chirality, giving 2-phenylpropanol with 93% ee. When compared to the results obtained with their (Rp,S) counterparts (76 and 62% ee) the existence of a cooperative effect is evident in the former ligands. The absolute configuration of the major enantiomer is determined by the element of central chirality.

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Rozenberg synthesized an (Sp,Sp′) methylene-bridged bis[2.2]paracyclophane (141), a biphenol analogue, which was tested in the enantioselective addition of diethylzinc to benzaldehyde with 15 mol% ligand in the presence of titanium tetraisopropoxide, in toluene at −30 °C. Results were very modest, 2-phenylpropanol being obtained with a maximum ee of 36%213, 214, 226. Contrastingly, the spirophenol (R)-SPINOL (142) used by Ramón and others213, 222 was much more effective for the enantioselective alkylation with 20 mol% ligand in dcm at 0 °C. Using benzaldehyde and several p-substituted derivatives, products were obtained with ee in the 80–88% range.

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The addition of alkynylzincs to unsaturated aldehydes is promoted by (S, S)-ProPhenol (143), a chiral {ONONO}-type ligand developed by Trost227, 228. By treating the ligand with dimethylzinc, a bimetallic catalyst is formed that coordinates both aldehyde and alkyne. A wide variety of α,β-unsaturated and aromatic aldehydes and alkynes react in the presence of this reagent yielding the corresponding propargylic alcohols in high chemical and optical yields. Reactions were carried out using dimethylzinc in toluene at 3 °C. With aromatic aldehydes, alkynylation products were obtained with good yields and ee above 82%, the highest being 99% when 2,6-dimethoxybenzaldehyde was the substrate. For α,β-unsaturated aldehydes, ee were mostly above 86%, the highest being 95% when 2-bromo-3-phenylacrylaldehyde was alkylated. Likewise, the use of structurally different alkynes gave very satisfactory results. Due to this great versatility, it has been possible to use this methodology with ProPhenol in the total synthesis of several natural products229-231.

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Chiral tridentate {ONO} Schiff base ligands obtained through the condensation of salicylaldehyde derivatives with (S)-valinol (144a–g) and (S)-t-leucinol (144h–k) have been synthesized by Tanaka and coworkers232, 233. The enantioselective alkylation of benzaldehyde was carried out with diethylzinc in the presence of 5 mol% of these ligands, in hexane at 0 °C. The (S)-valinol derivatives gave good conversions to 2-phenylpropanol and ee of 56–90%. While the (S)-t-leucinol derivatives gave identical conversions, the ee for the products were all higher, 94–96%, the most efficient 144i giving the products with 96% ee. Even when the amount of ligand was reduced to 1 mol%, no detrimental effect on the yield or selectivity was observed. To determine the scope of 144i, it was used in the alkylation of an array of aromatic, heteroaromatic and aliphatic aldehydes. High yields and ee were obtained for all substrates, no significant difference being noted between the different types of aldehydes. The best result was with 2-naphthylaldehyde, which gave the alkylation product with 99% yield and 96% ee. Neither the high yields nor the high selectivities were affected by introducing electron-donating (OMe) or electron-withdrawing (Mef) substituents on the phenyl group (R2) of ligands 144i and 145a–d. The high catalytic efficiency was preserved after the structural changes, even when the ligand loading was reduced to 0.1 mol%.

Structurally similar to the above-mentioned ligands are the chiral tridentate {ONO} Schiff bases 146 obtained from the condensation of 3,5-di-t-butylsalicylaldehyde with chiral ethanolamine-derived amino alcohols. These ligands were tested in the alkynylation of aldehydes with dimethylzinc and phenylacetylene, in toluene at −20 °C. The ligand, 10 mol%, was used in the presence of Ti(OPr-i)4 in a ratio of 1:1.5234. Conversions to the corresponding propargyl alcohols were very good, 80–90%, the ee of the products being in the range of 78–88% when 146a was used. For 146b, with the opposite stereochemistry at C1, ee was <31%. For 146c, with the same stereochemistry at C1 as 146a and with one of the phenyl groups replaced by isopropyl, ee = 60-72%. The results show that while the substituent at C1 affects the ability of induction of the ligand, the strongest influence is related to the stereochemistry of this chiral center, a cooperative effect being observed when it has opposite stereochemistry to that of C2.

Chiral C1-symmetric ferrocenyl Schiff bases 147 were prepared by Kim and coworkers and used in the asymmetric addition of diethylzinc to aromatic aldehydes235. Benzaldehyde was alkylated in the presence of 10 mol% 147, in toluene at 0 °C, to give 2-phenylpropanol with ee = 54-98%, the highest result due to 147c, containing a diphenylphosphine substituent. The authors refer to a cooperative interaction of this group with zinc as being responsible for the high level of asymmetric induction. When higher or lower reaction temperatures were used, both the conversion and the enantiomeric excess diminished. Substituted aromatic aldehydes were also tested using 147c as catalyst. Products with 22–84% ee resulted, showing that any substituent on the aromatic ring of benzaldehyde lowers the selectivity of the process, with both electronic and steric factors being apparently responsible.

The chiral tridentate {ONO} reduced Schiff bases 148 have been used in enantioselective alkylations with diethylzinc by Yang and collaborators236. Benzaldehyde underwent the most efficient alkylation using 10 mol% of ligand 148b in toluene at room temperature, with 98% yield and 96% ee. Ligand 148a, however, catalyzed 2-phenylpropanol formation with only 84% conversion and 53% ee. When 148b was used in the alkylation of other aldehydes, excellent yields, 80–98%, and selectivity, mostly above 90%, were obtained. The lowest ee resulted when o-chloro- and o-bromobenzaldehyde were the substrate, 80 and 60%, respectively. These comparatively low values are attributed to both steric hindrance and electrostatic effects. Contrastingly, when ligands 148 were used in the alkynylation of benzaldehyde, the corresponding propargyl alcohols were obtained with only 6% ee, albeit with moderate to high yield.

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Tridentate {ONO} Schiff bases 111 derived from (+)-α-pinene were synthesized and used in the alkylation of benzaldehyde by Jaworska and coworkers175. Carrying out the reaction under optimized conditions, with 20 mol% of ligand in toluene at −70 °C, followed by reaction at room temperature, the most efficient ligand 111d gave only a moderate yield of product, 55%, with a low ee of 36%. The various isomers of methoxybenzaldehyde as well as the o- and m-halogen substituted benzaldehydes also gave products with moderate yields and very low ee. However, when the substrate was p-bromobenzaldehyde and p-chlorobenzaldehyde, products with moderate yields and ee of 90 and 82%, respectively, were obtained, indicating a very limited substrate scope for these ligands.

Novel chiral {NO}-bidentate o-(aminoalkyl)phenols 149 have been efficiently synthesized by several authors. The catalytic activity was initially tested in the enantioselective alkylation of aldehydes with diethylzinc using 6 mol% of ligand in toluene at room temperature237-239. Using benzaldehyde as substrate, conversions of 73–96% were obtained with ee of 5–89%, the best result being with 149e. Optimized reaction conditions, with 20 mol% of the ligand, gave the ethylation product in 94% yield and 91% ee. The alkylation of a variety of aldehydes, under the described conditions, proceeded with good results, giving product yields of 81–95% and 72–94% ee. Aromatic aldehydes with electron-donating substituents gave better ee values, 86–94%, and branched aliphatic aldehydes gave higher enantioselectivities than linear ones.

The o-(aminoalkyl)phenols 150, primary amine analogues of 149, have also been tested in the enantioselective alkylation of benzaldehyde in the presence of 10 mol% of ligand, in toluene at room temperature238. Conversions to 2-phenylpropanol were mostly low to moderate, with the exception of 150c where all substituents are t-butyl, which gave the product with 65% conversion and 93% ee. Various aromatic aldehydes were alkylated with 150c under optimized reaction conditions (10 mol% of ligand, 1:1 toluenehexane solvent, at −17 °C). Reactions proceeded with high enantioselectivity with aldehydes having an electron-withdrawing or electron-donating group at the p-position, all up to 99% ee. However, o-substituents lowered ee of the product, possibly due to steric hindrance. The effect of m-substituents, on the other hand, was small.

Yang used 150c in the enantioselective alkynylation of different aromatic aldehydes in order to determine the effect of the substrate structure on the outcome of the reaction240. Using phenylacetylene, diethylzinc, 10 mol% of ligand and 10 mol% of 1,8-bis(dimethylamino)naphthalene (proton sponge) to promote the formation of the alkynylzinc species, in dcm at room temperature, p-chlorobenzaldehyde gave the corresponding propargyl alcohol in 96% yield and 88% ee. Using other o-, m- and p-substituted benzaldehydes as substrate, the enantioselectivity of the process was found to depend on both the electronic and steric effects of the aldehyde substituents. Accordingly, p- or m-substituted substrates with electron-withdrawing groups afforded higher enantioselectivity than those with electron-donating groups. Best results were obtained with p- and m-nitrobenzaldehyde, 99% ee. However, a substrate with the same substituent in the o-position gave the corresponding propargyl alcohol with an ee of only 36%.

Hitchcock241, Arai242 and their collaborators used chiral backbones of (1R, 2S)-ephedrine, (1R, 2S)-norephedrine and 1,1′-binaphthyl for the synthesis of β-hydroxysalicylhydrazones, which were subsequently tested as catalysts in the enantioselective addition of diethylzinc to aldehydes. Reactions catalyzed with ephedrine derivatives (151) were carried out using 10 mol% of ligand in toluene at room temperature, while for those catalyzed with 1,1′-binaphthyl derivatives (152), 5 mol% of ligand was used at 0 °C. Ligand (151c) with an electron-withdrawing substituent on the aromatic ring was found to be the most selective ligand, giving 2-phenylpropanol in 78% ee. The electron-donating R1 groups on 151b and 151d gave rise to products with lower ee than when 151a with R1 = H was used (11, 61, and 65% ee, respectively). The presence of the more bulky isopropyl group on the nitrogen (151e) did not enhance chiral induction. Among the 152 ligands, the most selective was 152a which gave the product alcohol with 58% ee. The overall increase in steric bulk in this type of ligand, due to the presence of the 1,1′-binaphthyl moiety, seems undesirable.

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Schiff bases with camphorsulfonamide (153) and isoborneolsulfonamide (154) moieties were synthesized by Sun and coworkers to catalyze the alkylation of benzaldehyde with diethylzinc243. The ligands include two groups, one with the camphor backbone itself and the other with the corresponding hydroxylated backbone. Reactions carried out in the presence of 10 mol% of the 153 ligands in hexane at 0 °C showed moderate yield (46–66%) and selectivity (35–61% ee). Overall, 154 ligands, with a hydroxyl instead of a keto group, gave under the same conditions 2-phenylpropanol with higher yield (68–92%) and selectivity (45–90% ee). The ee of the products follow a similar trend, 153 giving products with 35–61% ee and 154, 45–90% ee. Another factor that seems to influence both the selectivity and reactivity of these ligands is the substitution pattern and type of substituents on the Schiff base moiety of the ligand. Accordingly, while ligands bearing electron-withdrawing substituents give lower enantioselectivities, those with electron-donating substituents enhance the asymmetric induction. On the other hand, ligands with o- and p-substituents give lower enantioselectivities than those with m-substituents.

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Ligands 153 and 154 were also tested by Sun in the alkynylation of aldehydes243. The reaction of benzaldehyde with phenylacetylene and diethylzinc was carried out in the presence of 10 mol% of chiral ligand and 30 mol% Ti(OPr-i)4, in toluene at room temperature. Contrary to the alkylations, in these reactions 153 gave better results, the unsubstituted 153a giving the corresponding propargyl alcohol with 86% ee. Using other aldehydes, moderate to high yields and ee of 68–90% were obtained for all of the products. Aromatic aldehydes bearing electron-withdrawing groups in the p-position gave products with higher enantioselectivity than those with electron-donating groups. Aliphatic aldehydes gave moderate yields and moderate to high ee. When the ligand loading was increased to 15 mol%, slightly higher ee values resulted.

3.3 Enantioselective Nitroaldol (Henry) Reactions

The enantioselective addition of a nitroalkane to the carbonyl group of aldehydes or ketones, the Henry reaction, produces chiral β-nitro secondary alcohols (equation 15). Of special importance is the asymmetric Henry reaction, which gives versatile intermediates in synthetic organic chemistry. β-Nitro alcohols can be easily converted into other compound families by reduction of the nitro group to amine, oxidation of the nitro group to aldehyde, ketone or carboxylic acid through the Nef reaction, or elimination of water to give β-nitroalkenes.

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Several types of chiral catalysts have been used to promote the nitroaldol reactions, namely BINOL and derivatives, bis(oxazolines), cinchona alkaloids, salen complexes, amino alcohols, Trost's ligand and Schiff bases244-246.

Zhou and coworkers247 reported the first asymmetric Henry reaction catalyzed by copper complexes of 155, {ONO}-type tridentate Schiff bases obtained from l- and d-phenylalanine. Catalysts with ligands 155a–c were tested under optimized reaction conditions, with p-nitrobenzaldehyde as model substrate, 5 mol% catalyst and 5 equiv of nitroalkane in ethanol at room temperature. p-Nitrobenzaldehye and nitromethane in the presence of the CuII − 155a complex afforded the β-nitro alcohol in 85% yield and 78% ee. Using CuII155c, results were quantitatively identical, but with the opposite absolute configuration of the product. In the presence of the CuII155b complex, with bulky t-butyl substituents, the yield was identical but only 64% ee was obtained. These results show that the absolute configuration of the products is determined by the chirality of the ligand and very bulky substituents are detrimental to stereoselectivity. Various aromatic aldehydes were tested using the more efficient catalysts, the copper complexes of 155a and 155c, to determine the scope of the reaction. Results showed that both are identically efficient for most of the tested aldehydes, regardless of electron-donating or electron-withdrawing substituents, giving products with moderate to good yields, 43–90%, and ee, 67–86%. Groups in the o-position give products with slightly higher ee, while aliphatic aldehydes give products with lower ee.

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In order to further test the influence of the aromatic ring substituents of the ligand on the outcome of the Henry reaction, more were synthesized with different R substituents on the phenyl group (155d–155m)248. Using identical optimized reaction conditions, it was confirmed that these substituents, especially R1, have no influence on the conversion, but they greatly affect the selectivity. Best results were observed when R1 was methyl; increasing steric hindrance lowered both the conversion and the ee of the product. The various aromatic aldehydes used gave products with yields of 67–87% and ee of 84–92%. As in previous studies, aliphatic aldehydes gave slightly lower yields and ee.

Çolak and Demirel249 prepared some simple Schiff bases (156a–156c) from salicylaldehyde and the commercially available amino alcohols (1S, 2R)-2-amino-1,2-diphenylethanol, (S)-phenylglycinol and (R)-2-amino-1,1,3-triphenylpropanol, respectively. p-Nitrobenzaldehyde reacted with nitromethane in the presence of 10 mol% of the copper complexes of these ligands, in dcm at room temperature, to give the corresponding β-nitro alcohol. Moderate conversions, 52–61%, and ee up to 82% were obtained for the CuII156c complex. Addition of NEt3 as a promoter resulted in higher yields but this was accompanied by a drastic reduction in the ee of the product.

Guo and Mao250 prepared additional Schiff base ligands (156d–156f) with structural variations of the aldehyde moiety and of the N-bonded backbone. The Henry reaction was carried out between 4-nitrobenzaldehyde and nitromethane, with 10 mol% of the catalyst, in isopropanol at 50 °C. With the CuII complexes of ligands 156b and 156d–f, which are structurally similar to those of Çolak and Demirel249, moderate conversions and ee of 5–77% were obtained. In the presence of the CuII156b complex, the product was obtained with 81% ee. The same complex, previously used by Çolak, gave 62% ee, the improvement most certainly being a consequence of the change in solvent from dcm to isopropanol. Complexes of 157 and 158, holding, respectively, hydroxyindanyl and hydroxynaphthyl substituents, gave moderate conversions with low stereoselectivity. More bulky ligands, such as those with t-butyl groups, were less efficient in all cases.

The substrate scope was widened to other nitrobenzaldehydes, as well as fluoro- and chlorobenzaldehydes, and cinnamaldehyde. With the most efficient catalyst of the CuII156b complex, yields were moderate to good and products with ee 62–81% obtained, with the exception of 2,4-dichlorobenzaldehyde, which gave an ee of 34%, possibly due to steric hindrance.

Trost and Yeh251 used the binuclear zinc complex of (S, S)-ProPhenol (143) in the reaction of nitromethane with aromatic and aliphatic aldehydes. Under optimized conditions (5 mol% of catalyst, 10 equiv of nitromethane, in thf at −35 °C) aromatic and heterocyclic aldehydes gave β-nitro alcohols in good yields, 69–79%, and ee of 78–93%. Aliphatic aldehydes and α-branched aldehydes gave nitoaldol products with very good ee, 84–93%, while yields of product were higher with the α-branched aldehydes than with the unbranched ones.

To evaluate the influence of the structure on the outcome of the nitroaldol reaction, new ligands were prepared and tested by Trost and coworkers252. Using ligands that retained the diphenylcarbinol moieties of 143, while varying the phenol substituents, little effect was observed on yields and ee, except in the case of the p-methoxy substituent, which caused a dramatic decrease of both, and the p-fluoro derivative, which showed a slight ee increase.

With ligands that retained the phenol and changed the diphenylcarbinol moiety to naphthyl, biphenylyl and p-fluorophenyl, it was the biphenylyl-substituted ligand that gave the best result, 90% ee for the β-nitro alcohol product.

Jammi and collaborators253 synthesized Schiff bases 40a–40c and 156g–156i from 3,5-di-t-butylsalicylaldehyde and commercially available (S)-amino alcohols. The reaction of p-nitrobenzaldehyde with nitromethane in the presence of 2.5 mol% of the CuII complexes of these ligands, in dcm at room temperature, showed 40a to be the best ligand, giving the corresponding β-nitro alcohol in 90% yield and 66% ee. The reaction of other aldehydes in the presence of the best catalyst was also studied. Benzaldehyde, as well as o-, m- and p-substituted derivatives with electron-donating and electron-withdrawing groups, all underwent reaction with 84–95% yield and 54–76% ee, the best selectivity being observed for m-nitrobenzaldehyde. Other aromatic aldehydes gave up to 81% yield and 61% ee.

Copper complexes 161 of chiral oxazoline-Schiff bases were prepared in situ by Yang and coworkers254 by reacting oxazolines (159) with salicylaldehydes (160), followed by treatment with copper acetate (equation 16). p-Nitrobenzaldehyde reacted with nitromethane in the presence of 10 mol% catalyst, in ethanol at room temperature, to give the corresponding product with 90–98% yield and ee up to 69% when the copper complex of 159b + 160d was used. When the scope of this catalyst in the Henry reaction was tested using various aromatic aldehydes as substrate, β-nitro alcohols were obtained in moderate to good yields, 43–97%, and ee of 75–92%. Aromatic aldehydes with strong electron-withdrawing groups gave better results than those with weak electron-withdrawing or electron-donating groups.

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Zhang and coworkers255 prepared some ligands of C1-symmetry (162). These {NNO}-ligands are only tridentate in the corresponding copper complexes, because the pyridyl nitrogen does not coordinate with the metal center but instead establishes intermolecular H-bonds. In the reaction of p-nitrobenzaldehyde with nitromethane, in the presence of 5 mol% catalyst in ethanol at room temperature, products were formed in 42–95% yield and 7–96% ee. The p-pyridyl ligand 162 gave the best results, 95% yield and 96% ee, while the o-pyridyl ligand 162 was the least. The best catalyst was tested with other aldehydes, giving β-nitro alcohols with 63–96% yield and 85–99% ee. Aldehydes with electron-withdrawing substituents gave products with higher yields and selectivity, while those with electron-donating substituents gave lower yields but maintained the high selectivity. The tested aliphatic aldehydes, n-BuCHO, t-BuCHO and c-HexCHO, gave high yields and excellent ee (98–99%).

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Xin and collaborators256 tested copper complexes of some [2.2]paracyclophane Schiff bases (163) in the enantioselective Henry reaction. Using 10 mol% catalyst in dcm at room temperature, p-nitrobenzaldehyde reacted with nitromethane to give the corresponding nitro alcohols in 30–85% yield and 6–81% ee, best results being obtained in the presence of the copper complex of 163e, 85% yield and 90% ee. When this catalyst was tested with other substrates, results showed that aromatic aldehydes with electron-donating groups gave lower reactivity and stereoselectivity, while excellent yields and stereoselectivities, up to 94% ee, were obtained for substrates with strong electron-withdrawing groups. As in most cases, aliphatic aldehydes were not good substrates with this catalytic system.

Arai and collaborators257 prepared a library of immobilized phenolic ligands containing an imidazoline moiety. Chloromethylated imidazolines were immobilized onto a poly(styrenesulfonyl) support and treated with (R)- and (S)-α-methylbenzylamine followed by reductive alkylation with salicylaldehyde, 5-t-butylsalicylaldehyde, 5-bromosalicylaldehyde and 3,5-dibromosalicylaldehyde, to give a series of sixteen different ligands (164–168), the copper complexes of which were evaluated as catalysts in the asymmetric Henry reaction. The reaction of nitromethane with o-nitrobenzaldehyde using 5.5 mol% catalyst, in isopropanol at room temperature, proceeded with moderate to good yields but the highest selectivity was only 40% ee with supported 168, derived from 3,5-dibromosalicylaldehyde. However, the analogous unsupported copper complex 168 afforded high ee, 75–95%, for various aromatic aldehydes, with either electron-donating or electron-withdrawing substituents. Moreover, with this catalyst, aliphatic aldehydes gave nitroaldols in good yields with high selectivity, 80–91% ee.

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4 Hydroamination: Addition of Amines to Alkenes

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References

The great interest in the synthesis of nitrogen compounds is due to their high relevance in biological systems, pharmaceuticals and industrially important basic and fine chemicals. The metal-catalyzed hydroamination, involving the direct addition of amine N–H functionalities to unsaturated carbon–carbon double and triple bonds (Scheme 2), has become especially important because it is a green pathway, free of wastes and presenting high atom efficiency. These reactions may occur in intermolecular or intramolecular fashion, constituting simple and direct pathways to amines, enamines and imines.

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Scheme 2. Metal-catalyzed hydroamination reactions

Although the hydroamination process is energetically favorable, it is entropically disfavored. The direct hydroamination therefore has some barriers258. While activated carbon-carbon multiple bonds may suffer direct addition of amines, unactivated ones require catalysis in order to overcome the high activation energy of the process.

Many catalysts have been used for hydroaminations involving early and late transition metals, lanthanides and actinides. Early transition metal complexes, particularly of titanium259 and zirconium260, have proven successful catalysts for intramolecular hydroamination of aminoalkenes and for both inter- and intramolecular hydroamination of aminoalkynes and aminoallenes. These complexes show a very good functional group tolerance. While initially complexes with cyclopentadienyl ligands were mostly used, more recently complexes other than metallocenes have proven efficiency as catalysts in hydroaminations261.

Organolanthanide and organoactinide complexes display high catalytic efficiency for intramolecular hydroamination reactions of alkenes, alkynes and aminoallenes. In contrast to early transition metals and lanthanide complexes, late transition metal complexes have the advantages of being more stable, having higher functional group tolerance and being especially efficient with activated alkenes and alkynes.

There have been many reports of intramolecular hydroamination (cyclization) reactions catalyzed by metal complexes. The intramolecular processes are generally more favorable and therefore the cyclization of aliphatic and aromatic aminoalkenes and aminoalkynes has received more attention than the intermolecular reactions.

The iridium phosphinophenolate complex 169 was used by Hesp and coworkers262 to carry out the intramolecular hydroamination of unactivated alkenes with secondary alkylamine sidechains. Good conversions (>80%) to the corresponding pyrrolidine were observed, using 1 mol% catalyst in 1,4-dioxane at 110 °C (equation 17). In the substrates, increased steric bulk of the β-carbon substituents R and R1 favors cycloamination (Thorpe-Ingold effect)263-265, allowing lower catalyst loadings. Under the same reaction conditions, the RhI complex analogue of 169 gave quantitative yields; however, the pyrrolidine derivative was not the sole product, an isomerization product being the major one. Upon attempting a chiral version of this hydroamination with 170, identical activity was observed, but without any chiral induction in the product.

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Magnesium complexes 171 of {NNO}-tridentate ligands are efficient in the hydroamination/cyclization of 2,2-diphenylpent-4-enylamine with 3–10 mol% catalyst in benzene at room temperature266. With the sterically demanding SiPh3 group, 171b showed the highest activity. In the presence of more hindered substrates, such as the N-benzylated amino alkene derivative, higher reaction temperatures are required. Lanthanide complexes of salicylaldimine-type ligands267, 268 have been successfully used by several authors. O'Shaughnessy used yttrium and lanthanum complexes of 172 in the hydroamination/cyclization of 2,2-dimethylaminopent-4-ene in benzene at 70 °C. Low conversions to the product were observed. Lauterwasser and collaborators hydroaminated alkenes and alkynes with scandium complexes of 173a and 173b, with moderate and good catalyst activity, respectively268. While alkynes required only room temperature for the transformation, the alkenes demanded a higher temperature of 100 °C for identical results. Even though these complexes are chiral at the ScIII center, no enantioselectivity was observed in the reaction products. On the contrary, structurally similar reduced N[BOND]Me derivatives of these salicylaldimine-type ligands, 174 and 175, gave complete conversions to the pyrrolidine product. Once again, in spite of the chirality of these catalysts, only the LaIII174 complex gave a product with moderate stereoselectivity, 61% ee. Various secondary amine substrates were found to undergo hydroamination/cyclization in the presence of 10 mol% of chiral complex ZrIV-175, to give pyrrolidines and piperidines, in bromobenzene at 100 °C258, 259, 269, 270. All reactions gave complete conversion, with ee of 14–82%. Primary amine substrates, however, did not react in the presence of this catalyst.

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Bis(aryloxy)titanium complexes of 176a–176g were used as catalysts for the intermolecular hydroamination of 1-octyne with various primary amines271-273. Using 20 mol% of Ti(NEt2)4 and 10 mol% of the ligands in toluene at 100 °C, quantitative conversions were obtained. The use of ligands 176a–176g, carrying substituents with different degrees of steric demand, showed that the product regioselectivity could be controlled between Markovnikov and anti-Markovnikov behavior (equation 18), the former being favored in the presence of high steric demand (R1, R3 = t-Bu, i-Pr).

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The bis(pyrimidyloxy)titanium (177a) and zirconium (177b) complexes, inspite of being considered structurally similar to the complexes of ligands 176, have a very distinct behavior274-276. Use of 177a as catalyst results in very good yields of the Markovnikov product in the hydroamination of alkynes with arylamines. With alkylamines, however, the regioselectivity is lower and anti-Markovnikov products are also obtained. Catalyst 177b was less active than the titanium counterpart, giving no reaction for alkylamines and incomplete reactions for arylamines, with very good selectivities for the Markovnikov product.

Many catalysts used in asymmetric hydroaminations are based on complexes of lanthanide and early transition metal ions with bisphenolate ligands. The simplest structures are derivatives of 2,2′-biphenol with one or more substituents on the aromatic rings. In the hydroamination of 2,2-dimethylaminopent-4-ene, at 135 °C in the presence of 178, good yields of pyrrolidine were obtained277, 278. The highest activity resulted for M = ZrIV (96% yield), and a relatively low ee was observed for M = TiIV (26%); for M = ZrIV or HfIV selectivity was very low.

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Catalysts 179 showed greater activity than 178 in the hydroamination of alkenes, requiring lower reaction temperatures. The highest activity was observed for 179b, but the highest ee (36%) resulted in the presence of 179a258, 259, 261, 279-281. Complex 179c exhibited activity in the intermolecular hydroamination of 1-octyne, giving the product imine with good to excellent yields. The Markovnikov/anti-Markovnikov selectivity was found to depend on the primary amine used273.

Various types of biphenol-derived aminophenolate complexes have also shown interesting results in hydroamination reactions. The salen analogue bisphenolate-metal complexes 180a–180c of LaIII, YIII and SmIII showed poor activity and very low enantioselectivity when used in the hydroamination/cyclization 2,2-dimethylpent-4-enylamine267, 279. The studies of Wang and coworkers282, using the chiral zirconium complex of the Schiff base 181, also resulted in poor activity with the same substrate, the maximum conversion in 48 h being only 24% and the product ee 15%. Contrastingly, samarium and yttrium complexes of Schiff base-type ligand 182, where a salicylaldehyde moiety is substituted by a pyrrol unit, gave good to excellent conversions. The SmIII complex was the most active in the conversion to the pyrrolidine, with 37% ee. On the other hand, the ytterbium complex resulted in moderate conversions, but a higher ee, 43%. This trend is identical when substrates that lead to 6-membered rings are used: higher conversions when the metal is samarium and higher ee when it is ytterbium279, 283.

Salan analogue complexes 183 and 184 are more efficient than the salen analogue complexes 180 and the corresponding complexes of Schiff base ligand 181, giving complete conversions of the substrates in the hydroamination/cyclization under similar reaction conditions258, 259, 267, 270, 275, 279. Complexes 183a and 184a give products with ee of up to 61% and 82%, respectively.

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5 Diels–Alder Reactions

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References

The Diels–Alder reaction was discovered in 1928 by Otto Diels and Karl Alder and is one of the most versatile synthetic transformations in organic chemistry. In the decades of 1980 and 1990, the catalytic enantioselective version of this reaction was exploited and several chiral Lewis acids were used to catalyze Diels–Alder reactions. Complexes of aluminum and boron with chiral ligands were the first to be used, but nowadays transition metal-based complexes are preferred284, 285. Several types of metal complexes are used to promote Diels–Alder reactions, with chiral and non-chiral ligands such as BINOL (1,1′-bi-2-naphthol) and TADDOL (α,α, α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanol) derivatives, oxazolines, salens and Schiff bases.

Jacobsen and coworkers286, continuing their studies on enantioselective hetero-Diels–Alder reactions (HDA)287, used a Cr complex of Schiff base 104i for the synthesis of several dihydropyran derivatives (equation 19). Using 5 mol% of the complex, in the presence of molecular sieves 4A, excellent diastereoselectivity (endo:exo > 96:4) and an ee of 94% were obtained for adduct 186a in the absence of solvent. The reaction was extended to a wide range of α,β-unsaturated aldehydes (185b–185o), resulting in high enantioselectivities (89–98%) and moderate to high yields (40–95%).

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Jacobsen and Joly288 reported the use of the CrIII − 104i complex enantiomers for the synthesis of diastereoisomeric dihydropyranones (equation 20). Using Danishefsky's diene (187), several chiral aldehydes and both enantiomers of 104i, it was possible to obtain both diastereoisomers of the product (188) with good diastereoselectivities.

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The CrIII104i complex was used by Chavez and Jacobsen289 for the HDA reaction between substituted cyclopentenecarboxaldehydes (189) and ethyl vinyl ether (equation 21). In the model reaction between 189 (R = H) and ethyl vinyl ether, the cycloadduct (190) was obtained with excellent diastereoselectivity (endo:exo = 97:3) and 87% ee. When rac-189 (R = Me) was used in the same reaction, a 1.2:1 ratio of diastereoisomers was obtained. In each case the major diastereoisomer was obtained with very good to excellent ee (80% and 98%).

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Chromium(III) complexes of 104i were also used by Jacobson and coworkers290 in the enantioselective DA reaction of quinone 191 with diene 192 (equation 22). It was found that different chromium complexes could be formed, depending on the milieu. In aqueous solution, a dimeric complex was formed that gave good results for the HDA reaction (equation 19) but poor results for quinone DA reactions. Catalysts prepared in acid media with 3M HCl afforded a pseudo-octahedral monomeric complex with two water molecules and a chloride ligand that showed good results for quinone DA reactions (for the product 193, 12:1 regioselectivity and 96% ee). The scope of the reaction was evaluated for several quinones and dienes with good results: regioselectivities ranging from 9:1 to 30:1 and ee from 86–97%290. Metal complexes of 104i have also been used in the DA synthesis of various precursors in the total synthesis of chiral compounds of pharmacological interest291-309.

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Feng and coworkers reported the use of several Schiff base ligands for the synthesis of chiral δ-lactones (195) by HDA reaction of Brassard diene 194 with aromatic aldehydes (equation 23)310. Reaction conditions were optimized and from all the metal alkoxides tested titanium isopropoxide showed the best results. Ligands 104d, 146a and 196a–196d were tested using diene 194 and benzaldehyde as substrates and a catalyst loading of 20 mol% in dcm. Under these conditions, 146a afforded 195 in 76% yield and 93% ee. The reaction was extended to other aromatic aldehydes, giving products with moderate to good yields (24–87%) and high ee (90–97%).

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Feng and coworkers311 reported the use of 104d, 146a, 196a–k and 197a for the same reaction. Again, 146a was the most efficient for the HDA reaction of diene 191 with benzaldehyde. The catalyst loading could be reduced to 5 mol% with almost the same yield (71%) and ee (93%). Other aromatic and aliphatic aldehydes were used, and again high ee were obtained for aromatic aldehydes (87–99%), while aliphatic aldehydes and p-nitroacetophenone gave very poor results.

The same authors312 described the use of CuII complexes of 104d, 104i, 146a, 196d, 197a–d, 198 and 199 for the HDA reaction of another Brassard diene (200) with several aldehydes to yield adducts 201 (equation 24). Higher ee values were obtained with 104d and 104i using benzaldehyde as dienophile (80% and 75%, respectively). Reaction conditions were optimized and with 104i it was possible to improve the yield (up to 70%), the ee (97%) and the diastereoselectivity (anti:syn = 94:6) by lowering reaction temperature to −78 °C and using toluene as solvent. Ligand 104i proved to be very efficient for the majority of aromatic aldehydes studied, giving products with diastereoselectivities anti:syn = 88:12 to 99:1 and excellent ee (91–99%), except for o-methylbenzaldehyde and 1-naphthaldehyde (ee of 54% and 24%, respectively). For these aldehydes, 104d with a less bulky substituent (t-Bu instead of adamantyl) gave better ee values (94% and 92%, respectively). Moderate ee values were obtained for aliphatic aldehydes, 73% for n-butyraldehyde and 62% for (E)-but-2-enal.

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Recently CrIII -complexes of 104f, 104i and 202 were used in HDA reaction between Danishefsky's diene 187 and several aldehydes313 (equation 20). Two counterions were used, Cl and BF4, the latter showing higher yields. Better results were obtained with 104i, using AcOEt as solvent at 50 °C. The DA adduct resulting from the reaction between Danishefsky's diene and benzaldehyde was obtained in 91% yield and 90% ee. The reaction was extended to other aldehydes, both aromatic and aliphatic, resulting in DA products with high yield (78–99%) and ee (75–97%).

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Ding and coworkers314 prepared several titanium complexes of Schiff bases 203a–203u to catalyze asymmetric HDA reactions between Danishefsky's diene 187 and several aldehydes. Using 10 mol% of TiII203a complex with molecular sieves 4A, in toluene, and 5 mol% of benzoic acid as additive, an 80% yield and 85% ee was obtained in the reaction of 187 with benzaldehyde. Ligands with R1 = H (203a, 203e, 103h and 203m) were the most effective in the HDA reaction giving products with ee from 85 to 91%. Best results were obtained for this process with the same catalysts, using (S)-2-(6-methoxy-2-naphthyl)propionic acid (Naproxen) as carboxylic acid additive (quantitative yields of 188 (R = Ph) with 93–97% ee).

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Various aromatic, aliphatic and olefinic aldehydes were used in the HDA reaction with very good yields and enantioselectivities. Ding's research group315 prepared ligands 204a–204d, derived from 203a by introducing a simple benzyloxy substituent (204a and 204b) or dendritic substituents (205) of various sizes (204c and 204d), and used them in the HDA reaction of aldehydes with Danishefsky's diene 187. Good results were obtained in all cases for benzaldehyde, with 204d denditric ligands proving to be superior to the analogous ligands. Increasing the size of the 5-substituent did not significantly affect the ee (95% for 204b and 97% for 204d n = 1). The titanium complex of 204d n = 1 was used with substrates other than benzaldehyde and very good ee values (90–97%) were obtained in all cases.

In addition to Schiff base ligands there is also reference in the literature to the use of several arene-ruthenium complexes of salicyloxazolines (206a–206e) in asymmetric Diels–Alder reactions of cyclopentadiene with methacrolein or bromoacrolein316. The effects of the arene (mesitylene, p-cymene or benzene) and the ligand were evaluated; best results were obtained with p-cymene and 206b. The enantioselective DA reaction between cyclopentadiene and methacrolein or bromoacrolein, using 2 mol% of catalyst at 0 °C, gave an ee of 48% and 53%, respectively.

Yamatsugu and coworkers317 reported the use of metal complexes of 119d, 207a and 207b for the DA reaction between diene 208 and dimethyl fumarate (209) as dienophile (equation 25). The endo (210a) product of this reaction is an important precursor for the synthesis of Tamiflu®. Several metal isopropoxides were screened and the best results were obtained with Ba(OPr-i)2. An ee of 88% for the desired endo product (210a:210b = 3:1) was obtained with 30 mol% of BaII207b in thf. The effect of additives was studied; thus, when CsF was used, the catalyst loading could be reduced to 2.5 mol%, with 91% yield, in 4:1 diastereoisomeric ratio, and 97% ee for the endo product 210a.

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Complexes of achiral phenolates have also been used as catalysts in Diels–Alder reactions. Bull and colleagues described the synthesis and catalytic activity of phenolate ligands 211a–211c, analogous to 64, in several DA reactions. Complexes of titanium triflate-211b318 were used in aza-DA reactions between Danishefsky's diene 187 and several imines (equation 26). Using 10 mol% of catalyst, DA adducts were obtained in good yields (56–73%) in less than 1.5 h. Bull and coworkers319 later described the use of the same catalyst in a three-component one-pot aza-DA reaction between benzaldehyde, benzylamine and Danishefsky's diene to give 1-benzyl-2-phenyl-2,3-dihydropyridin-4(1H)-one in 69% isolated yield. The titanium triflate-211b complex was also used in several conventional DA reactions with good results. Reaction of 2,3-dimethyl-1,3-butadiene and N-phenyl-maleimide or α,β-unsaturated N-acyl-oxazolidin-2-ones, in the presence of 20 mol% of catalyst, afforded the corresponding cycloadducts in good isolated yields (68–96%). Reaction of cyclopentadiene with α,β-unsaturated N-acyl-oxazolidin-2-ones or (S)-4-benzyl-N-but-2-enoyloxazolidin-2-one gave the corresponding products in high endo/exo selectivities and yields.

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Lanthanide complexes of diphenolate 212 were synthesized and used in DA reactions of cyclopentadiene with substituted dienophiles320, 321. The best stereoselectivities were obtained with neodymium complexes and yields from 54% to 93% were obtained for the dienophiles studied.

Several aluminum complexes of {OSO}-tridentate ligands 213 were prepared and used in the DA reaction of cyclopentadiene with methacrolein322. AlMe3 and Al(i-Bu)3 were used as precursors and the complexes were prepared either in thf or AcOEt. For all complexes studied, the exo adduct was obtained as the major regioisomer with moderate conversions.

6 Miscellaneous Processes Catalyzed by Metal Phenolates

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References

The group of catalysts classified as metal phenolates has been used in a great variety of synthetic processes. Coverage of the literature over the past ten years showed a greater incidence of the use of these catalysts in certain processes (oxidations of alkenes, sulfides, alcohols and alkanes, additions of trimethylsilylcyanide, diorganozincs and nitroalkanes to C[DOUBLE BOND]O and C[DOUBLE BOND]N bonds, hydroaminations and Diels–Alder reactions). However, metal phenolates have also found some use in other catalytic processes.

6.1 Cross-coupling Reactions

The reaction of organometallic reagents with organic electrophiles in the presence of metal ion catalysts is considered a method of choice for the formation of a wide range of C[BOND]C, C[BOND]H, C[BOND]heteroatom or C[BOND]M bonds, commonly referred to as cross-coupling reactions. Occasionally, metal phenolates have been used to catalyze some of these processes.

Metal complexes of simple salicylaldehyde-derived {NO} bidentate Schiff bases (analogous to the ligands of complex 76 used in the oxidation of alcohols) have been used in Suzuki- and Sonogashira-type coupling reactions, giving products in moderate to good yields. PVC-supported and Merrifield resin-anchored metal complexes, similar to 26 and 27 used in epoxidation reactions, have found some application in Suzuki–Miyaura- and Kumada-type carbon–carbon bond-forming reactions. Several substrates undergo cross-coupling reactions with these catalysts to give moderate to good yields of the corresponding product. The catalysts can be easily recovered and used for various cycles without activity loss323-328.

Iron complexes of amine bisphenolates (analogous to 65 and 66 used in sulfoxidations) with an additional dangling donor group were used in Kumada-type cross-coupling reactions. The yields of coupling products were found to be very variable, depending mostly on the type of dangling donor group present329.

Palladium complexes of {NNO} tridentate Schiff bases were tested in the Suzuki–Miyaura cross-coupling reaction. Under optimized conditions, these reactions afforded very good yields330. Structurally similar to the previous ligands, {ENO} Schiff base complexes of palladium, platinum, ruthenium and mercury (where E = S, Se, Te) were applied in the Heck and Suzuki reactions. In the Heck reaction, when ArI was used, very good yields of products resulted with all metal complexes, while overall low yields were observed in the Suzuki coupling with these catalysts331.

6.2 Transfer Hydrogenations and Hydrogenations

Alcohols are very important building blocks in the synthesis of fine chemicals and pharmaceuticals. The transfer hydrogenation and hydrogenation with molecular hydrogen are among the most common methods of obtaining alcohols from aldehydes and ketones. The success of these reactions depends mostly on the appropriate combination of a metal ion and a ligand. Therefore, considerable efforts have been invested in the development of efficient transition metal complexes as catalysts for this type of reaction. Among the types of catalysts explored are some metal phenolates.

Arylazophenolate ligands (similar to 78 used in the oxidation of alcohols) may coordinate metal ions in an {NO}-bidentate fashion or, under forced conditions, these ligands undergo C[BOND]H activation, usually by ruthenium(III), leading to the formation of cyclometalated compounds. These complexes catalyze the transfer hydrogenation of a variety of aliphatic and aromatic ketones, in the presence of isopropanol/KOH, at 80–82 °C, with conversions of 70–99%332-334.

The catalytic reactivity of a series of ruthenium(III) complexes of general structure Ru(L)2X(EPh3), where E = P or As, X = Cl, Br and L = bidentate Schiff bases similar to 76, was explored in the transfer hydrogenation of imines, giving the corresponding amines with moderate to good conversions335.

Palladium(II) complexes of Schiff bases prepared from 3,5-di-t-butylsalicylaldehyde and o-, p-substituted anilines were used in the hydrogenation of nitrobenzene, in dmf, at room temperature and 1 atm, giving complete conversion to aniline336.

A palladium Schiff base complex prepared from salicylaldehyde and modified chloromethylated poly(styrene-divinylbenzene) was found to be effective in hydrogenation of various terminal linear and cyclic alkenes at 25 °C and 1 atm, and could be recycled several times without significant loss in its activity337.

Ruthenium complexes of chiral {PNO} Schiff base ligands derived from substituted salicylaldehydes and (R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethylamine were employed in the asymmetric transfer hydrogenation of ketones, in isopropanol/KOBu-t, at 80 °C, giving up to 99% conversion and 94% ee with 1-naphthyl methyl ketone as the substrate338.

(Arene)ruthenium(II) reduced Schiff base complexes are efficient catalysts in the transfer hydrogenation of acetophenone in isopropanol/KOH at 80–82 °C with conversions of 70–98%339.

A ruthenium(III) complex bearing an amine-bis(phenolate) tripodal ligand was examined in the transfer hydrogenation of various aliphatic and aromatic ketones, giving the corresponding alcohols with conversions greater than 90% in the presence of isopropanol/KOH at reflux340.

6.3 Diverse Catalyzed Reactions

Chromium(III) complexes of 104i have been used by Jacobsen and collaborators to catalyze the asymmetric hetero-ene reaction between aromatic or aliphatic aldehydes and silyl enol ether derivatives, to give rise to β-hydroxytrimethylsilyl enol ethers in high yields and enantioselectivities up to 96%341, 342.

The gadolinium(III) complexes of halogenated derivatives of 119 can efficiently catalyze the enantioselective conjugate addition of cyanide to enones in thf at −20 °C. By manipulating reaction conditions such as the CN source and the temperature, it is possible to selectively produce 1,4-adducts with high yield and enantioselectivity up to 98%343. The same complexes are also used in the enantioselective conjugate addition of cyanide to α,β-unsaturated N-acylpyrroles, in EtCN, at −20 °C, to give the 1,4-adducts in high yields and enantioselectivity up to 98%344. Yet another application of the Gd-119 complexes is the catalysis of the enantioselective desymmetrization reaction of meso-aziridines with TMSCN, at room temperature, in EtCN, to give the corresponding β-aminonitriles with ee up to 93%345.

References

  1. Top of page
  2. Introduction
  3. Oxidations with Metal Phenolates
  4. Additions to Carbonyl and Imine Groups
  5. Hydroamination: Addition of Amines to Alkenes
  6. Diels–Alder Reactions
  7. Miscellaneous Processes Catalyzed by Metal Phenolates
  8. References