CHAPTER 1
THE SAEGUSA OXIDATION AND RELATED PROCEDURES

Jean Le Bras and Jacques Muzart

Institute of Molecular Chemistry of Reims, UMR 7312, The National Center for Scientific Research (CNRS) and University of Reims Champagne-Ardenne, B.P. 1039, 51687, Reims Cedex, 2, France

1. Introduction
2. Mechanism and Stereochemistry
   1. Silyl Enol Ethers or Silyl Ketene Acetals as Substrates
      1. 1,4-Benzoquinone as the Oxidant
      2. Oxygen, Oxygen and a Copper Salt, or Oxygen and Oxone as the Oxidant
      3. Oxygen and tert-Butyl Hydroperoxide as the Oxidant
      4. Allyl Carbonate as the Oxidant
   2. Enol Acetates as Substrates
   3. Alkyl Enol Ethers and Vinyl Halides as Substrates
   4. Allyl Enol Carbonates, Allyl ß-Keto Carboxylates, or Allyl Malonates as Substrates
   5. a-Chloro Ketones as Substrates
3. Scope and Limitations
   1. Silyl Enol Ethers or Silyl Ketene Acetals as Substrates
      1. Palladium(II) and 1,4-Benzoquinone or Copper Salt (Methods A and B)
      2. Palladium Acetate, DMSO, and Oxygen (Method C)
      3. Palladium(0)/SiO2 and Oxygen (Method D)
      4. Palladium(II) Acetate, Oxone, and Oxygen (Method E)
      5. Palladium(II) Hydroxide, tert-Butyl Hydroperoxide, Oxygen, and a Base (Method F)
      6. Palladium(0) Complexes and Diallyl Carbonate (Method G)
      7. Atypical Dehydrogenation Reactions
      8. Comparison of the Aforementioned Procedures
   2. Enol Acetates as Substrates
   3. Alkyl Enol Ethers as Substrates
   4. Allyl Enol Carbonates, Allyl ß-Keto Carboxylates, or Allyl Malonates as Substrates
   5. a-Chloro Ketones as Substrates
4. Applications to Synthesis
   1. Desymmetrization/Palladium-Mediated Dehydrosilylation Reaction Sequence
   2. Enones as Intermediates in Natural Product Synthesis
   3. Tandem Reactions Involving Enones
   4. Saegusa Reaction on an Industrial Scale
5. Comparison with Other Methods
6. Experimental Conditions
   1. Silyl Enol Ethers as Substrates
   2. Enol Acetates as Substrates
   3. Allyl Enol Carbonates as Substrates
   4. Allyl ß-Keto Carboxylates as Substrates
7. Experimental Procedures
   1. 1. 5,5-Dimethyl-3a´,4´-dihydro-1´H-spiro[[1,3]dioxane-2,2´-pentalen]-5´(3´H)-one [Stoichiometric Dehydrogenation of a Ketone via a Silyl Enol Ether].
      2. 4-Isopropylcyclohex-2-enone [Dehydrogenation of a Ketone in the Presence of Benzoquinone via a Silyl Enol Ether].
      3. 1,4-Dioxaspiro[4.5]dec-6-en-8-one [Catalytic Dehydrogenation of a Silyl Enol Ether in the Presence of an Allyl Carbonate].
      4. Bicyclo[4.1.0]hept-3-en-2-one [Catalytic Dehydrogenation of a Silyl Enol Ether in the Presence of tert-Butyl Hydroperoxide and Oxygen]
      5. (4R,5S)-5-Ethyl-4,5-dihydroxycyclohex-2-enone [Catalytic Dehydrogenation of a Silyl Enol Ether in the Presence of Oxygen]
      6. (1R,5R)-1-[(((1,1-Dimethylethyl)dimethylsilyloxy)methyl)]bicyclo[3.1.0]hex-3-en-2-one [Catalytic Dehydrogenation of a Ketone in the Presence of Oxygen via a Silyl Enol Ether]
      7. 4-Cyano-4-(3,4-dichlorophenyl)cyclohex-2-enone [Catalytic Dehydrogenation of an Enol Acetate in the Presence of an Allyl Carbonate]
      8. (4R,5S)-2-Allyl-4,5-bis((benzyloxy)methyl)-4,5-dimethylcyclopent-2-enone [Catalytic Decarboxylative Dehydrogenation of an Allyl ß-Keto Carboxylate]
      9. 6-[(Z)-7-[(Tetrahydropyranyl)oxy]hept-1,5-diyn-3-ene]-6-[(tert-butyldimethylsilyl)oxy]cyclohex-2-en-1-one [Catalytic Decarboxylative Dehydrogenation of an Allyl Enol Carbonate]
      10. (E)-6-Oxohex-4-en-1-yl Acetate [Catalytic Dehydrogenation of an Alkyl Enol Ether in the Presence of Benzoquinone]
      11. (E)-4-Phenyl-2-butenal [Catalytic Dehydrogenation of an Alkyl Enol Ether in the Presence of Cu(II)]
8. Tabular Survey
   1. 1. Table 1A. Acyclic a,ß-Unsaturated Ketones
      2. Table 1B. Cyclic 2,3-En-1-ones
      3. Table 1C. Heterocyclic 2,3-En-1-ones
      4. Table 1D. Cross-Conjugated Dienones
      5. Table 1E. Phenolic Systems
      6. Table 2. a,ß-Unsaturated Aldehydes
      7. Table 3. a,ß-Unsaturated Esters
      8. Table 4. a,ß-Unsaturated Lactones and Lactams
      9. Table 5. a,ß,?,d-Unsaturated Ketones, Esters, and Amides
9. References

Introduction

a,ß-Unsaturated carbonyl compounds are highly useful synthetic materials in organic synthesis,1-4 and regioselective dehydrogenation of carbonyl compounds to the corresponding a,ß-unsaturated carbonyl compounds is an important transformation in synthetic chemistry.5,6 One-pot, palladium-mediated dehydrogenation reactions of ketones, aldehydes, esters, lactones, and amides are known, but such reactions are limited primarily to simple substrates.7-11 Moreover, they suffer from lack of regiocontrol in the case of unsymmetrical ketones. In 1977, Ito, Hirato, and Saegusa reported the conversion of silyl enol ethers to the corresponding a,ß-unsaturated ketones and aldehydes using stoichiometric or substoichiometric amounts of palladium(II) salts.12 Although silyl enol ethers are easily prepared from saturated ketones or aldehydes, 12 several years passed before the first application of the Saegusa Reaction was reported. Studies to improve on the original procedure by using lower catalyst loadings have since appeared. A brief review of the Saegusa Reaction concerning the literature up to 1998 is available,13 and related methods devised primarily by the Tsuji and Larock groups are discussed in reviews14-16 and books. 6 17-19

This review concerns the Saegusa Reaction and related methods. In addition to enol silanes, enol acetates, alkyl enol ethers, allyl enol carbonates, allyl ß-keto carboxylates, allyl malonates, and a-chloro ketones have been transformed into a,ß-unsaturated carbonyl products. This chapter covers the literature through August 2018.

Mechanism and Stereochemistry

The mechanism of the formation of a,ß-unsaturated carbonyl compounds using palladium-mediated procedures related to the Saegusa Reaction is substrate-dependent, but a majority of known examples involve a palladium enolate as the key intermediate. Catalytic reactions have been developed under various conditions.

Silyl Enol Ethers or Silyl Ketene Acetals as Substrates

Most palladium-mediated, oxidative dehydrogenation reactions of silyl enol ethers and silyl ketene acetals use a palladium(II) salt. The coordination of the C=C bond to the palladium species results in transmetalation, which leads to loss of the silyl group and formation of a palladium enolate. 13 The latter compound exists as an equilibrium between the oxo-?3-allyl palladium and the C- and O-enolate tautomers (Scheme 1).20 Subsequent ß-hydride elimination affords the a,ß-unsaturated carbonyl compound and a hydridopalladium complex. Although the stability of palladium hydrides is ligand-dependent,21 they are converted, in most cases, to palladium(0) species. Because addition/elimination of hydridopalladium species to olefins is reversible, (E)-a,ß-unsaturated carbonyl compounds are usually produced selectively from acyclic substrates.

Scheme 1

To achieve a catalytic process, the Saegusa Reaction is carried out in the presence of an oxidant-often 1,4-benzoquinone or oxygen-to regenerate the active palladium(II) species. The proposed catalytic cycle generates AcOSiR3 and acetic acid (i.e., YSiR3 and HY of Scheme 1) as the byproducts of the first turnover and hydroquinone or peroxides as the stoichiometric byproducts. However, palladium(0) species can form relatively stable palladium(0)-alkene complexes, which can impede the catalytic cycle (Scheme 2).22 Such complexes can be decomposed on heating or treatment with silica gel.

Scheme 2

1,4-Benzoquinone as the Oxidant

Coordination of 1,4-benzoquinone to palladium(0) in the presence of acetic acid generates 4-hydroxyphenoxypalladium acetate (Scheme 3).23,24 This intermediate reacts with...