CHAPTER 1
Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray

Department of Science, Technological University of Dublin (TU Dublin), Dublin, Ireland

1. Formation and Reactions of Acetals and Related Species
2. Reactions of Glucosides
3. Reactions of Ketenes and Related Cumulenes
4. Formation and Reactions of Nitrogen Derivatives
   1. Imines: Synthesis, and General and Iminium Chemistry
   2. Mannich, Mannich-type, and Nitro-Mannich Reactions
   3. Other 'Name' Reactions of Imines
   4. Stereoselective Hydrogenation of Imines, and Other Reductive Processes
   5. Stereoselective Allyl-, Aryl-, Alkenyl-, and Alkynyl-ations of Imines
   6. Other Stereoselective Reactions of Imines
   7. Other Reactions of Imines
   8. Oximes
   9. Hydrazones and Related Species

1. CC Bond Formation and Fission: Aldol and Related Reactions
   1. Reviews of Aldols, and General Reviews of Asymmetric Catalysis
   2. Asymmetric Aldols
   3. The Mukaiyama Aldol
   4. The Morita-Baylis-Hillman Reaction
   5. Other Aldol-type Reactions
   6. Allylation and Related Reactions
   7. Alkynylations
   8. The Benzoin and Stetter Reactions
   9. The Michael Addition
   10. Miscellaneous Condensations

1. Other Addition Reactions
   1. Addition of Organozincs
   2. Arylations, and Addition of Other Organometallics, Including Grignards
   3. The Wittig and Other Olefinations
   4. Hydrosilylation, Hydrophosphonylation, Hydroboration, and Hydroacylation
   5. Formation of Cyanohydrins, Cyanosilylation, and other Cyanations
   6. a-Aminations and Related Reactions

1. Enolization, Reactions of Enolates, and Related Reactions
   1. a-Halogenation, a-Alkylation, and Other a-Substitutions

1. Oxidation and Reduction of Carbonyl Compounds
   1. Oxidation of Aldehydes to Acids
   2. Other Oxidations and Oxidative Processes
   3. Reduction Reactions
   4. Miscellaneous Cyclizations
   5. Other Reactions
   6. References

Formation and Reactions of Acetals and Related Species

?,d-Unsaturated aldehydes (e.g. 1) undergo endo-selective Prins bicyclization with aldehydes to give dioxabicyclo[2.2.2]octanes (2) in high de and ee. Glyoxylic esters work well (i.e. R?=?COCO2Et), with induction by a chiral BINOL-derived N-triflyl-phosphoramide at ambient temperature.1

Organocatalytic enantioselective routes to two classes of cyclic acetals have been described. Chiral 5,5-fused tetrahydrofurobenzofurans (bearing two stereocentres) and 5,6-bridged methanobenzodioxepines (bearing three) have been prepared from hydroxyarenes and ?-keto-enals. Using diphenylprolinol TMS ether as catalyst, very low loadings are required for these very efficient iminium catalyses. The pathways have been probed using DFT.2

Treatment of a-diazo-ß-ketoesters (3) with cyclic ketones, lactones, or carbonates (4; X, Y?=?CH2,O n?=?0-3) yields spiro ketals, orthoesters, or orthocarbonates (5). The key first step of diazo decomposition requires a catalyst combination of 1,10-phenanthroline and a ruthenium salt, [CpRu(MeCN)3]+[BAr4]-, where Ar?=?3,5-bis(trifluoromethyl)phenyl.3

Spiroacetalization of two enol ethers (6; n?=?1 or 2) has been the subject of a QM/MM study which compares two catalysts: a chiral phosphoric acid and a chiral imidodiphosphoric acid with a much more confined 'active site'. For the first catalyst (a BINAP-phosphoric acid with buttressing anthracenes), the ee is only 1% for the formation of the 5,5-spiro-system (7; n?=?1): the substrate is small, fits inside, and induction is negligible. In the second catalyst, the ee goes up to 92%, reflecting a confinement effect. The 6,6-reaction (7; n?=?2) shows a slightly higher ee of 95% for the second catalyst.4

Vinyl propynyl acetals (8) can be rearranged to yield catechol ethers (9) using gold(I) in 1,2-dichloroethane (DCE) at 25?°C. Alkyne activation triggers nucleophilic addition of acetal oxygen, setting up an equilibrium mixture of oxonium ions of similar stability. These can be considered as 'kinetically self-sorted' by the next step: highly exothermic cyclization. Computations support this view, as the barriers between the oxonium ions are low, so the system can be considered as an example of dynamic covalent chemistry (DCC), where the fast equilibration acts like an 'error-checking' process. The alkene 'linker' in the substrate can be replaced by an aromatic (or heteroaromatic), resulting in naphthyl analogues, etc. Syntheses of the substrate acetals (8) are also described.5

Enantiomeric acetals (10) show a surprising difference under reductive cleavage by diisobutylaluminium hydride. The a-acetal (PMP behind) is converted to a PMB ether, while the ß-acetal is resistant [but can be opened with Na(CN)BH3/TMSCl].6

Substituted benzothiophenes have been prepared from substituted thiophenoxy-acetaldehyde diethyl acetals, XC6H4SCH2CH(OEt)2, in the presence of polyphosphoric acid. The mechanisms have been probed by way of kinetic and computational studies.7

Proline catalyses reaction of dihydroxyacetone isopropylidene acetal (11) with enantiopure a-silyloxy aldehyde (12) to give a single isomer (13) cross-aldol product in 91% yield in a substantially aqueous medium at ambient temperature. This result has now been investigated by NMR spectroscopy, monitoring individual steps, allowing the role of water to be better understood. It is found that proline 'protects' aldehyde (12) as an oxazolidinone, but this means that the catalyst is effectively 'trapped' by aldehyde (12) ., but the high water content helps avoid this. Water also mediates prolyl group exchanges, and opposes dehydration of the aldol. NMR also allowed detection of a 'wanted' intermediate, an enamine of the adduct (14). The authors count two unfavourable effects of water countervailed by four favourable ones.8

BINOL-based trifluoromethyl aryl ketones (15; R?=?H or CH2OMe) act as fluorescence sensors for 1,2-diamines in organic solvents, with a dramatic increase at 375?nm and a decrease at 500?nm. Little effect is seen with other diamines (or monoamines), so diketones (15) can act as highly selective ratiometric sensors for 1,2-diamines, especially ethylenediamine. UV and NMR studies suggest formation of a hemiaminal (16) at the electron-deficient carbonyl, with stabilization by hydrogen bonding from the second nitrogen. Such a non-covalent interaction is absent for a monoamine, and would be poorly optimized for a longer diamine. Job plots for the fluorescence interaction suggest an unexpected 1:4 stoichiometry (rather than 1:2), indicating that the phenolic oxygens can also hydrogen-bond 1,2-diamines.9

Alkynylhemiaminals (17) can be prepared from propargyl aldehydes, or oxidatively from propargyl alcohols. The Meyer-Schuster reaction was then studied for stereoselective synthesis of ß-enaminones (18). Catalysed by Brønsted acids, the selectivity of this rearrangement has now been found to be very simply tuneable: benzoic acid gives (Z-18), while tosic acid gives (E-18). The key step is the protonation of the allenol intermediate (19). The mechanism is supported by 18O-labelling experiments.10

2-Substituted 2H-chromenes (20) have been prepared via aniline-catalysed nucleophilic attack on ortho-hydroxycinnamaldehydes, via N,O-acetals. The cyclization-substitution cascade accommodates a broad range of nucleophiles including indoles, pyrroles, phenols, and silyl enol ethers.11

Enantioselective aminomethylation of a,ß-unsaturated aldehydes, RCHCHCHO, by an N,O-acetal, Bn2NCH2OMe, to give a ß2-amino ester, RCH2*CH(CH2NBn2)CO2Me, has been reported to occur under NHC/Brønsted acid dual catalysis, but a theoretical investigation has surprisingly uncovered a specific role for the Brønsted base, refining the mechanism to an NHC/Brønsted acid/Brønsted base multi-catalysis.12

For a reactivity scale for N,O-acetals, see the 'a-Aminations' section.

A...