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 and Keteniminium Species
4. Formation and Reactions of Nitrogen Derivatives
   1. Imines: Synthesis, and General and Iminium Chemistry
   2. Reduction and Oxidation of Imines
   3. Mannich, Mannich-type, and Nitro-Mannich Reactions
   4. Addition of Organometallics to Imines
   5. Arylations, Alkenylations, Allylations, and Alkynylations of Imines
   6. Other Additions to Imines
   7. Aza-Baylis-Hillman Reactions of Imines, and their Morita Variants
   8. Staudinger and Aza-Henry Reactions, and Additions Involving Nitriles
   9. Insertion Reactions of Imines
   10. Cycloadditions of Imines
   11. Miscellaneous Reactions of Imines
   12. Oximes, Oxime Ethers, and Oxime Esters
   13. Hydrazones and Related Species
   14. Nitrones 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 Amino Acids and their Derivatives
   4. Asymmetric Aldols Catalysed by Other Organocatalysts
   5. Other Asymmetric Aldols
   6. The Mukaiyama Aldol
   7. The Henry (Nitroaldol) Reaction
   8. The Baylis-Hillman Reaction and its Morita Variant
   9. Other Aldol and Aldol-type Reactions
   10. Allylation and Related Reactions
   11. Alkynylations
   12. The Stetter Reaction and the Benzoin Condensation
   13. Michael Additions and Related Reactions
   14. Miscellaneous Condensations
6. Other Addition Reactions
   1. Addition of Organozincs
   2. Arylations
   3. Addition of Other Organometallics, Including Grignards
   4. The Wittig and Related Reactions
   5. Hydroacylations
   6. Hydrosilylations
   7. Addition of Nitrile-containing Species
   8. Phosphonylation and Related Reactions
7. Enolization, Reactions of Enolates, and Related Reactions
   1. a-Substitutions
8. Oxidation and Reduction of Carbonyl Compounds
   1. Oxidation of Aldehydes to Acids
   2. Oxidation of Aldehydes to Esters, Amides, and Related Functional Groups
   3. Baeyer-Villiger Oxidation
   4. Miscellaneous Oxidative Processes
   5. Reduction Reactions
   6. Stereoselective Reduction Reactions
9. Other Reactions
10. References

Formation and Reactions of Acetals and Related Species

1,11-Dihydroxy-undec-9-en-5-one derivatives (1; R = H, Me) undergo a novel and highly stereoselective palladium(II)-catalysed intramolecular cyclization via unstable hemiacetal intermediates, to give spiroketals (2).1

Conversion of aldehydes (RCHO) to their cyclic dithioacetals (3; X = R) has been simplified by the use of 2-chloro-1,3-dithiane (3; X = Cl) in dichloroethane at 50 °C, employing a simple iron catalyst, FeCl3. A single-electron transfer (SET) mechanism is proposed.2

Unsaturated spiroacetal (5) has been prepared as a single regioisomer with de > 96% from a cyclic acetonide (4) with an appropriate alkyne-alcohol tether; the arrowed oxygen is lost with the extrusion of acetone. Catalysed by gold(I), the reaction also works for non-cyclic alkyne-triol chains, but much less cleanly. The acetone acetonide preparative step can be considered to be a regioselectivity regulator, masking the 1,3-diol's alcohol groups.3

N-Boc-protected amino acid esters derived from serine and threonine forms (natural and unnatural) combine with tetramethoxyalkanes [1,2-diacetals: R1-{C(OMe)2}2-R2] to give chiral bi- and tri-cyclic N,O-acetals in high diasteriomeric excess (de), via an intramolecular trans-carbamoylation cascade.4

2-Substituted and 2,2-disubstituted 1,3-diols, HO-CH2-CR1R2-CH2OH, have been desymmetrized through their para-methoxy benzylidene acetals (6), using dimethyldioxirane (DMDO) to form an intermediate orthoester (7), followed by proton transfer using a chiral phosphoric acid to deliver the monoester product (8). Density functional theory (DFT) calculations indicate that the DMDO oxidation step is rate-determining, and a suitable auxiliary - a buttressed BINOL-phosphoric acid - gives yields/ee up to 99/95%.5

DFT has been used to study the thermal racemization of spiropyrans.6

Based on the reaction of a quinone monoacetal (9) with methylhydroxylamine hydrochloride (MeNHOH·HCl) to give a bridged isoxazolidine (10a) via a double hetero-Michael addition, the analogous diaza process was attempted, using the appropriate hydrazine MeNHNHMe(·2HCl) in refluxing acetonitrile. Surprisingly, this gave a new nucleophilic chlorination to yield a substituted chlorophenol (11) regio-selectively, presumably via acid-catalysed methoxide loss and chloride attack, or vice versa. The intended bridged pyrazolidines (10b) could be accessed via base catalysis in a protic solvent.7

Trimethylsilyl triflate is an efficient Lewis acid catalyst for oxygen-to-carbon rearrangement of vinyl and ketene acetals (12 and 13) to give chain-extended ketones or esters, respectively, giving fair yields in 30 min in dichloromethane (DCM) at -78 °C, with 0.01 mol% trimethylsilyl trifluoromethanesulfonate (TMSOTf). The method has been applied to stereoselective synthesis of C-glycosides from the corresponding anomeric vinyl ethers. Starter (12) can be prepared by methenylation of the corresponding acetal-ester with Tebbe's reagent, and (13) via elimination of an appropriate ß-iodo-acetal.8

Selective Heck arylation of acrolein diethyl acetal in water has been achieved by appropriate choice of base: sodium acetate favours reaction with cinnamaldehydes, while diisopropylamine works with 3-propionic esters. In the presence of such a base, the ligands in the [Pd(NH3)4]Cl2 catalyst are exchanged.9

Alkynyldimethylaluminium reagents, derived from terminal alkynes and trimethylaluminium, doubly add to N,N-disubstituted formamides, or to the corresponding O,O-acetals, while similar N,O-acetals undergo mono-addition.10

Alkynylation of N,O-acetals and related pro-electrophiles has been carried out using Au(I) carbophilic catalysts, LAuX, with specific counteranions, X- = -OTf or -NTf2.11

A study of nucleophilic substitutions of five-membered ring acetals bearing fused rings indicates that subtle changes in the structure of the latter can dramatically affect de. An unconstraining ring allowed selectivity comparable to a non-fused analogue, with 'inside' attack on the oxocarbenium ion, but if the second ring included at least one oxygen, the de fell considerably. DFT-calculated transition states (TSs) for the addition of allyltrimethylsilane correlated with the results, which are also compared with the better known six-membered series.12

An experimental and theoretical study examines why silylated nucleobase additions to acyclic a-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol, opposite to that expected for the corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues.13

A new oxidant, N-chloroisonipecotamide, has been characterized and tested with benzaldehyde di-n-alkyl acetals in acetonitrile: kinetic orders are first and zero, respectively.14

An easily prepared and handled palladium(II) complex has been used for the deprotection of acetals and dioxolanes while leaving acid-sensitive groups unaffected.15

For reports on acetals termed 'aziridine aldehyde dimers', see the Ugi reaction under 'Imines: Synthesis and General and Iminium Ion Chemistry' section. For preparation of bicyclic acetals via an acetalization/oxa-Michael process, see 'Michael Additions and Related Reactions' section.

Reactions of Glucosides

The 'formose reaction', in which formaldehyde is dimerized to glycolaldehyde (HOCH2CHO) and onward to sugar-like substances, is a candidate for prebiotic simple sugars. Though a mechanism was proposed by Breslow in 1959,16a it has remained controversial. New deuterium studies have clarified the route, retaining the original intermediates but changing some connecting steps. Glycolaldehyde formation is autocatalytic, and...