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Reactions of Aldehydes and Ketones and Their Derivatives

M. G. Moloney

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford Oxford Suzhou Centre for Advanced Research, Jiangsu, P.R. China

CHAPTER MENU

• Formation and Reactions of Acetals and Related Species
• Reactions of Glucosides
• Reactions of Ketenes and Related Cumulenes
• Formation and Reactions of Nitrogen Derivatives
• Imines: Synthesis and General and Iminium Chemistry
• Mannich and Mannich-Type Reactions
• Stereoselective Hydrogenation of Imines, and Other Redox Processes
• Cyclizations of Imines
• Other Reactions of Imines
• Oximes, Oxime Ethers, and Oxime Esters
• Hydrazones and Related Species
• Iminium Ion Chemistry
• C-C Bond Formation and Fission: Aldol and Related Reactions
  • The Asymmetric Aldol
  • The Morita-Baylis-Hilman Reaction and Its Aza-Variants
  • Other Aldol and Aldol-Type Reactions
  • The Michael Addition
• The Wittig and Other Olefinations
• Miscellaneous Additions
• Reactions of Enolates and Related Reactions
• Oxidation of Carbonyl Compounds
• Reduction of Carbonyl Compounds
• Miscellaneous Reactions
• References

Formation and Reactions of Acetals and Related Species

The gold-catalyzed cyclization of 2-alkynylarylaldehyde cyclic acetals (1) leads to indenone derivatives (2) in good-to-excellent yields (Scheme 1). The cyclization occurs via a 1,5-H shift, favored by the cyclic acetal group, which both activates the benzylic C-H bond and prevents alkoxy migration.1 A detailed study of the mechanism of this process has been investigated using density functional theory calculations. The reaction proceeds by initial coordination of Au(I) to the alkyne, which induces a 1,5-H shift (the rate-determining step), the rate of which depends on the electronic environment. Cyclization, 1,2-H shift, and then elimination lead to product formation; however, an aryl group on the alkyne is required for rapid reaction; otherwise, the cyclization becomes thermodynamically disfavored.2

Scheme 1

Scheme 2

The cyanation of cyclopropanone acetals (3) giving ß-carbonyl nitriles (4) with excellent enantioselectivity has been reported (Scheme 2). Mechanistically, a ring opening of an intermediate cyclopropanoxy radical leads to a benzylic radical, which is followed by cyanation.3 The ring opening of donor-acceptor cyclopropanes (5) using 1,3-cyclohexanedione cyclic ketals and thioketals (6) as O- and S-nucleophiles, respectively, catalyzed by Cu(OTf)2, leads to alkylene glycol diethers and dithiol diethers (7) in good to high yields under mild conditions (Scheme 3).4 The selective ring opening of a cyclic acetal (8) with TMSOTf and NEt3 leads to vinyl ether (9) and can be applied to the synthesis of highly functionalized nucleoside vinyl ethers (Scheme 4).5

Scheme 3

Chiral 2,3-dihydro-1,4-dithiine derivatives (10) are available by the reaction of chiral cyclic hydroxy dithioacetals in the presence of boron trifluoride diethyl etherate (Scheme 5), in a mechanism involving internal nucleophilic SN2 substitution of the hydroxyl group by sulfur and then formation of a bicyclic thiiranium cation, ring expansion, and dimerization.6

Tandem Prins cyclizations for the construction of fused scaffolds have been reviewed.7 A review describes Pd-catalyzed anti-Markovnikov oxidations of aromatic and aliphatic terminal alkenes to give terminal acetals (oxidative acetalization) and aldehydes (Wacker-type oxidation). Importantly, the addition of electron-deficient cyclic alkenes such as p-benzoquinones and maleimides facilitates nucleophilic attack of oxygen nucleophiles on coordinated terminal alkenes and also serves to oxidize Pd(0) depending on the reaction conditions. The steric demand of nucleophiles, slow substrate addition, and halogen-directing groups are also key parameters.8

Scheme 4

Scheme 5

Reactions of Glucosides

Hydrogen bonding in carbohydrate systems has been of interest. Vacuum ultraviolet (VUV) electronic circular dichroism (ECD) spectra of D-glucose, a-D-glucopyranose, and ß-D-glucopyranose were measured in aqueous solution down to 163 nm using a synchrotron radiation VUV-ECD spectrophotometer. Theoretically calculated spectra (using molecular dynamics (MD) simulations with explicit water molecules and time-dependent density functional theory (TDDFT)) reproduced the experimentally observed spectra and confirmed that VUV-ECD distinguished the a-anomer and ß-anomers and the three gauche (G) and trans (T) rotamer conformations (GT, GG, and TG) of the hydroxymethyl group at C-5. This was possible from changes in the degree of hydration of intramolecular hydrogen bonds around the hydroxymethyl group and the hydroxyl group at C-1.9 Using ab initio MD simulations, it has been shown that for three D-glucose isomers (a, ß, and open chain) in 1-ethyl-3-methylimidazolium acetate solution in the presence and absence of water, every hydrogen bond elongates, except the glucose-glucose hydrogen bond for the open chain and the a-form, which both shorten, indicating the beginning of crystallization. The glucose ring rearranges from on-top to in-plane, and the open form changes from a coiled to a more linear arrangement.10 The hydration of glucosamine has been studied by Car-Parrinello MD, which shows that the hydroxyl groups form stable hydrogen bonds with the water molecules with intensities ranging from weak (closed-shell interaction) to intermediate (partially covalent interactions). The main contribution to stabilizing energies comes from n s* hyperconjugation, and the energy barrier for the proton transfer from water to the amino group is 0.88 kcal mol-1. This low protonation energy barrier shows that glucosamine can be protonated in an aqueous environment at room temperature.11 Using cellulose (an infinitely repeating polymer of D-glucose) as an example, MD modeling has been used to show that the thermal excitation of intermolecular stretching modes leads to lengthening and weakening of intermolecular O-H?O hydrogen bonds, indirectly strengthening the associated covalent O-H bonds; this is responsible for temperature-dependent blue shifting of O-H stretching bands in the IR spectra of carbohydrate biopolymers.12

DFT calculations have been used to understand anomerizations and mutarotation equilibria and, importantly, show the role not only of the aldehyde intermediate but also its hydrated form, which is often more abundant in the equilibrium. Moreover, different mutarotation mechanisms may operate for every monosaccharide, and pyranose-furanose interconversion may actually occur without the intermediacy of open-chain forms. For D-glucose, D-ribose, and D-xylose, all structures involved in mutarotation undergo interconversion pathways, whose energy barriers calculated at the M06-2X/6-311++G(d,p) level are in good agreement with previous experimental measurements.13

Glycosylation reactions in a series of bicyclic C-2-substituted pyranoside models are best understood by the bent bond/antiperiplanar hypothesis orbital model, which invokes hyperconjugation interactions between groups at C-2 and the two t bonds (bent bonds) of oxocarbenium ion intermediates formed under the glycosylation conditions. Thus, nucleophiles add to oxocarbenium intermediates by SN2-like antiperiplanar displacement of the weaker of the two t bonds.14 The activation of both "armed" and "disarmed" type glycals toward direct glycosylation may be controlled by the choice of oxidation state and counterion of a copper catalyst; the process gives deoxyglycosides in good to excellent yields. Mechanistic studies show that CuI is essential for effective catalysis and stereocontrol and that the reaction proceeds through dual activation of both the enol ether and the hydroxyl nucleophile.15 A review covering the chemoenzymatic production of fluorinated carbohydrates, focusing on activated fluorinated donors and enzymatic glycosylation involving fluorinated sugars as either glycosyl donors or acceptors, has appeared.16 The trifluoromethylation of glycals using CF3SO2Na as the trifluoromethyl source and MnBr2 as the redox mediator under electrochemical conditions in 60-90% yields with high regioselectivity has been reported. The reaction proceeds by a radical mechanism.17 A note that the use of the term electron-donating benzyl groups is misguided has appeared and that benzyl ethers (OBn) should more correctly be referred to as...