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Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray

School of Chemical and BioPharmaceutical Sciences, Technological University of Dublin (TU Dublin), Dublin, Ireland

CHAPTER MENU

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 and Mannich-type Reactions
   3. Stereoselective Hydrogenation of Imines, and Other Reductive Processes
   4. Cyclizations of Imines
   5. Other Reactions of Imines
   6. Oximes, Oxime Ethers, and Oxime Esters
   7. 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. The Asymmetric Aldol
   3. The Morita-Baylis-Hillman Reaction
   4. Other Aldol and Aldol-Type Reactions
   5. Allylation and Alkynylation Reactions
   6. The Michael Addition
6. Other Addition and Related Reactions
   1. Arylations
   2. The Wittig and Other Olefinations
   3. Hydroboration and Hydroacylation
   4. a-Aminations and Related Reactions
   5. Miscellaneous Additions
7. Reactions of Enols, Enolates, and Related Reactions
   1. Tautomerism
   2. Enol Ethers, Enol Esters, and Enolates
   3. a-Halogenation, a-Alkylation, and Other a-Substitutions
8. Oxidation of Carbonyl Compounds
   1. Oxidation of Aldehydes to Acids
   2. Cross-dehydrogenative and Related C-C Coupling Processes, and C()-H Activations
   3. Other Oxidations and Oxidative Processes
9. Reduction of Carbonyl Compounds
10. Miscellaneous Cyclizations
11. Other Reactions
12. References

Formation and Reactions of Acetals and Related Species

A hemiacylal-type species (1, from Ph-CH2-O-CHMe-CO2H) was formed in a study of photocatalytic decarboxylative acetoxylation of aliphatic carboxylic acids, employing copper(II) catalysis and a hindered acridinium cation in a single electron transfer (SET) process.1

Some preliminary results in trithioester exchange with thiols, and in metathesis between trithioesters, have been described. The reactions are discussed in terms of their potential, as tools for dynamic covalent chemistry.2 Acetal metathesis is also described, particularly in the context of making polyacetals via acetal metathesis polymerization (AMP).3

C-Alkynyl-N-Boc N,O-acetals, R1-C=C-CCH(OR2)NHBoc, have been reacted with oxonium ylides (generated in situ from a-diazoketones) to give polyfunctional propargyl-amines. A rhodium(III)/chiral Bronsted acid catalyst system gives high yields/des/ees.4

Reactions of Glucosides

A short tutorial/review (55 references) describes advances in stereo- and regio-selective glycosylation with protection-less sugar derivatives.5 A review (38 references) describes the development of glucose transport inhibitors, which are potentially useful for selective attack on cancer cells (due to their altered metabolism and enhanced glucose demand), and other medical conditions.6 Synthetic strategies for regio- and stereo-selective fluorinations of sugars have been reviewed (73 references), focusing on reaction mechanisms and biological applications.7

The possibility of inosine tautomerism in water has been investigated by computation, including an exploration of relevant conformational space, inosine-water clusters, hydrogen bonding, and comparisons with the gas phase. The 6-enol tautomer appears to be accessible via an asynchronous concerted route.8

An unusual 1,5- or 1,6-alkyl transposition has been reported along with acetalization of 3-deoxy glycals, using TMSOTf as Lewis acid. Although the mechanism has not yet been pinned down, the transformation opens up routes to 2-C-branched bicyclic acetals of various deoxy-sugars, and to 2-C-branched levoglycosans.9

In a total synthesis of saffloneoside, an unusual para-hydroxycinnamylcyclopentenone C-glucoside, a stereospecific acyloin contraction was found to be controlled by the glucose moiety.10

A glycosyl fluoride has been activated for glycosylation using indium(III) triflate. This mild, nontoxic catalyst allows the process to occur under ambient conditions, stereoselectively, without pre-activation or additives, and with simple workup.11

Unprotected mono- and di-saccharidic carboxamides undergo transamidations with primary and secondary arylic, heterocyclic, and aliphatic amines without solvent or catalyst, producing only ammonia as by-product. A known epimerization at the a-position is a limitation of the method.12

A new route to trifluorinated glucopyranose analogues has been developed, starting from inexpensive levoglucosan and using a Chiron approach. The dominant conformation was established for each. Lipophilicities were then measured, using 19F-NMR spectroscopy to determine log P: significant variations were seen, with four isomers varying between -0.64 and -0.18.13

ß-D-Glycosaminosides have been prepared via a 2,4-nitrobenzenesulfonamide-directed SN2-type displacement with good stereoselectivity. Examples from the gluco- and galacto-series are reported.14

Novel triazole-fused iminocyclitol-d-lactams have been prepared and tested as glycosidase inhibitors.15

Pyrolysis of holocellulose produces carboxylic acids and alcohols. Acetic acid and glycerol were selected as representative compounds in a DFT study of secondary reactions arising from such species during pyrolysis. Glycerol can produce vinyl alcohol, acrolein, acetaldehyde, and acetol by various paths, and can also catalyse reactions of acetic acid.16

Such pyrolysis also allows isomerizations between isomers of monosaccharides to occur, and a computational study of the rates and equilibria of such processes indicates that barriers are significantly lowered if a hydroxy group within the monosaccharide participates, or an external R-OH group, including that of water. The equilibrium constants calculated indicate that higher temperatures favour furanoses, and also linear aldehyde forms.17

Stereoselectivity in glycosylation with deoxofluorinated glucos- and galactos-azide thiodonors has been investigated by low-temperature NMR for the case of the Tf2O/Ph2SO promoter system, with the formation of covalent a-triflate and both anomers of oxosulfonium triflate being observed. The selectivity depends on the configuration of the glycosyl donor and on the reactivity of the acceptor: reactive ones favour 1,2-trans-ß-glycosides for both D-gluco and D-galacto donors, while poorer acceptors favoured 1,2-cis-a-glycosides with D-galacto donors (but were unselective with D-gluco donors).18

4-O-Glycosylated 2-pyrones have been synthesized by a gold(I)-catalysed intermolecular rearrangement of glycosyl alkynoic ß-ketoesters.19

A pyrrolidine salt converts 2-deoxyribofuranoses to 2-deoxyribofuranosides via a furanosyl oxocarbenium ion, trapped with various alcohols: a-selectivity varies from complete to non-existent, and the reasons are discussed. An unexpected ß-selectivity in the case of 2-cyanoethanol is explained in terms of a nitrile effect.20

C-Glycosides have been prepared by a carbonylative Negishi-type coupling of 2-iodoglycals and alkyl or aryl halides, using catalysis by palladium and base.21

Cascade aldol reactions of aldopentoses with methyl ketones have been studied by QM simulation, using both L- and D-proline as catalysts, and identifying matched and mismatched cases. The mechanism identified includes Mannich, proline hydrolysis, retro aza-Michael, and oxa-Michael steps.22

A range of anthocyanidins (e.g. 2) and anthocyanins (glycosides of anthocyanidins) have been prepared and tested as inhibitors of a-glucosidase. Some proved quite potent: (2) exhibits IC50 = 14.4 µM, holding out potential application for diabetes. Fluorescence quenching and in silico studies have been used to characterize the binding.23

Similar studies have been undertaken for compounds isolated from the bark...