Chapter 1
Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray

Department of Science, Institute of Technology, Tallaght (ITT Dublin), Dublin, Ireland

1. Formation and Reactions of Acetals and Related Species
2. Reactions of Glucosides
3. Reactions of Ketenes
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. Synthesis of Azacyclopropanes from Imines
   5. Alkylations and Additions of Other C-Nucleophiles to Imines
   6. Arylations, Alkenylations and Allylations of Imines
   7. Miscellaneous Additions to Imines
   8. Reduction of Imines
   9. Other Reactions of Imines
   10. Oximes, Hydrazones and Related Species
5. C-C Bond Formation and Fission: Aldol and Related Reactions
   1. Reviews of Aldols and General Reviews of Asymmetric Catalysis
   2. Asymmetric Aldols Catalysed by Proline and Its Derivatives
   3. Asymmetric Aldols Catalysed by Other Organocatalysts
   4. The Mukaiyama Aldol
   5. Other Asymmetric Aldols
   6. The Henry (Nitroaldol) Reaction
   7. The Baylis-Hillman Reaction and Its Morita-variant
   8. Other Aldol and Aldol-type Reactions
   9. Allylation and Related Reactions
   10. The Horner-Wadsworth-Emmons Reaction and Related Olefinations
   11. Alkynylations
   12. Stetter Reaction, Benzoin Condensation and Pinacol Coupling
   13. Michael Additions
   14. Miscellaneous Condensations
6. Other Addition Reactions
   1. Addition of Organozincs
   2. Arylations
   3. Addition of Other Organometallics
   4. The Wittig Reaction
   5. Hydrocyanation, Cyanosilylation and Related Additions
   6. a-Aminations and Related Reactions
   7. Miscellaneous Additions
7. Enolization, Reactions of Enolates and Related Reactions
   1. a-Halogenation, a-Alkylation and Other a-Substitutions
8. Oxidation and Reduction of Carbonyl Compounds
   1. Oxidation of Aldehydes to Acids
   2. Oxidation of Aldehydes to Amides, Esters and Related Functional Groups
   3. Baeyer-Villiger and Other Oxidation Reactions of Ketones
   4. Miscellaneous Oxidative Processes
   5. Reduction Reactions
   6. Stereoselective Reduction Reactions
9. Other Reactions
10. References

Formation and Reactions of Acetals and Related Species

Equilibria for the formation of hemiacetals from eight isomeric hexanals have been measured in methanol, and compared with the steric environment around the aldehyde.1 Kinetic studies have also been carried out, and these suggest an early TS.

Catalytic asymmetric acetalization of aldehydes has been demonstrated, using large chiral BINOL-derived phosphoric acid catalysts: these are proposed to generate confined chiral microenvironments.2

A new enantioselective arylation of enecarbamates (1) has been developed, using a quinone imine acetal (2) as a functionalized surrogate aromatic, and an axially chiral BINAP-dicarboxylic acid catalyst.3 The useful a-amino-ß-aryl ether products (3) are formed in up to 99% ee, and des often >90%, and are further transformable into chiral ß-aryl amines and a-aryl esters. Mechanistically revealing observations include: (i) trans-enecarbamate switches the sense of asymmetric induction; (ii) the NH in (1) is critical, presumably for hydrogen bonding to catalyst: the NMe starter fails; and (iii) crossover experiments fail, implicating an intramolecular route. The proposed first step is a highly stereoselective C-C bond formation followed by aromatization (with elimination of R3-OH), then re-addition of R3-OH to the sidechain.

A stable N,N´-diamidocarbene has been used to activate molecules with X-X homonuclear single bonds (where X = Br, O, S, C).4 Br2 yields a substituted tetrahydropyrimidinium salt, benzoyl peroxide yields diamidoacetal product, and various sulfides give the corresponding diamidothioacetals. For X = C, insertion into the (O)C-C(O) bond of diones was observed, and for cyclopropenone, insertion into the (O)-C-C bond occurred.

meta- and para-Substituted benzaldehyde acetals, X-C6H4-CH(OBu)2, have been oxidized by N-bromosuccinimide in acetonitrile, to give the corresponding esters (and alkyl bromide).5 Rates have been measured by the iodometric method, over a range of temperature. A primary kinetic isotope effect, kH/kD, is observed, indicating rate-determining C-H cleavage; a Hammett s value of 1 · 4 and activation parameters are given.

Kinetics of the oxidation of a range of aromatic acetals by N-chloronicotinamide have been measured in acetonitrile.6

The combination of triethylsilyltriflate with either 2,6-dimethylpyridine (2,6-lutidine) or 2,4,6-trimethylpyridine (2,4,6-collidine) effectively deprotects acetals of aldehydes under mild, neutral conditions, while leaving those of ketones unaffected.7 Pyridinium-type salt intermediates are proposed.

The Prins reaction has been modelled using DFT (density functional theory), using an alkene (RCH=CH2, R = Me or Ph), a formaldehyde dimer, and a proton-water cluster, H3O+(H2O)13. Both alkenes feature a concerted path to give the 1,3-diols. An unprecedented hemiacetal intermediate, HO-CH2-O-CH(R)-CH2CH2-OH, was then identified: it undergoes ring closure to the 1,3-dioxane product.8 Gas-phase Prins reaction of formaldehyde dimer with alkene has been studied computationally: it proceeds via a p-complex (without formation of any intermediate s-complex).9

DFT calculations have been used to study the kinetic and thermodynamic parameters of the oligomerization of formaldehyde in neutral aqueous solution: linear and cyclic oligomers up to tetramer were examined, and implications for enolization and aldol reactions were also examined.10

A series of new naphtha[1,3]oxazino[2,3-a]isoquinolines (4, R1 = H, Me, Ph, Ar; R2 = H, OMe) have been prepared from 1-aminomethyl-2-naphthols and 3,4-dihydro-isoquinolines.11 The predominant diastereomer is trans- (at the 7a- and 15-positions), but a surprising inversion at nitrogen can be observed by NMR (nuclear magnetic resonance). Computations support ring-opening at the C(7a)-oxygen bond, giving an iminium-phenolate intermediate.

For other reports of acetals, see the section titled 'Miscellaneous Oxidative Processes' later.

Reactions of Glucosides

Proton affinities and pKas have been calculated for various tautomers of d-glucose and d-fructose, and compare favourably with experimental measurements of the pH's of sugar solutions in water.12

A review surveys the catalysts and mechanistic approaches to alter the reactivity of hydroxyl groups in carbohydrates, thus facilitating regioselective manipulation.13

exo-Glycals [e.g., (Z)-5 and (E)-5] are glycosides with an exocyclic enol ether next to the oxygen of the ring, are useful synthons, and some have biochemical applications in their own right. However, the (E)-isomers have been inaccessible to date. In a treatment of the (Z)-species with strong base (aimed at further functionalization), t-BuLi at -78 °C surprisingly gave 34% conversion to the (E)-exo-glycal [(E)-5] with no by-products. A vinyl anionic intermediate was confirmed. Optimum isomerization employed 3 mol LiHDMS at ambient temperature for 10 min (to deprotonate), followed by -100 °C for 2 h, which favours the (E)-isomer.14

Several formic acid derivatives of a protected glucose have been prepared: O-perbenzoylated C-(ß-d-glucopyranosyl)-formimidate [6, R = C(=NH)OEt], -formamidine [R = C(=NH)-NH2], -formamidrazone [R = C(=NH-NHX)-NH2, X = H or Ts] and -formyl chloride (R = COCl).15 Designed to lead to 1,2,4-triazole derivatives of the sugar, they unexpectedly also gave 1,3,4-oxadiazole derivatives. DFT calculations have been used to investigate the alternative ring-forming pathways.

Chemo- and regio-selective functionalization of non-protected carbohydrates has been developed, allowing selective thiocarbonylation, acylation and sulfonylation of a particular carbohydrate in the presence of structurally similar carbohydrates, for example, anomers.16 For example, sugar anomers (7) can be functionalized in the 6-position in up to 99% yield and 99% ß-selectivity, using Me2SnCl2 as catalyst. Just switching the catalyst to Bu2SnCl2 gives comparable yields and a-selectivities in the 2-position. The mechanisms are discussed in terms of the steric approaches of the catalysts at the 1,2- versus 4,6-sites.

A DFT study of the acid catalysis of the mutarotation of erythrose and threose has...