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Reactions of Aldehydes and Ketones and their Derivatives

S. R. Hussaini

Department of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK, United States

CHAPTER MENU

• Formation and Reactions of Acetals and Related Species
• Reactions of Glucosides
• Reactions of Ketenes
• Formation and Reactions of Nitrogen Derivatives
  • Imines: General, Synthesis, and Iminium Chemistry
  • Mannich, Mannich-type, and nitro-Mannich Reactions
  • Other 'Name' Reactions of Imines
  • Alkylations
  • Miscellaneous Additions to Imines
  • Oxidation and Reduction of Imines
  • Other Reactions of Imines
  • Oximes, Hydrazones, and Related Species
• C-C Bond Formation and Fission: Aldol and Related Reactions
  • Asymmetric Aldol Reactions
  • The Mukaiyama Aldol
  • Other Aldol and Aldol-type Reactions
  • Alkynylations
  • Michael Addition and Miscellaneous Condensations
• Other Addition Reactions
  • Arylations
  • Addition of Other Organometallics, including Grignards
  • The Wittig, Julia-Kocienski, Peterson, and Other Olefinations
  • Hydrophosphonylation, Hydroboration, and Addition of Isocyanide
  • Miscellaneous Additions
• Enolization, Reactions of Enolates, and Related Reactions
  • a-Substitutions
• Oxidation and Reduction of Carbonyl Compounds
  • Oxidation of Aldehydes to Amides and Nitriles
  • Decarbonylation Reactions
  • Miscellaneous Oxidative Processes
  • Stereoselective Reduction Reactions
• Other Reactions
• References

Formation and Reactions of Acetals and Related Species

Novel nitrated [6,6,6]-tricyclic acetal or ketals are prepared by an intramolecular annulation of o-carbonyl allylbenzenes. The proposed mechanism involves olefinic nitration, bis-cyclization, and tautomerization, followed by another nitration. Further tautomerization and dehydration give the product. Non-cyclic products are obtained when the deoxygenated groups are at 4,5-position rather than 3,4-position on the benzaldehyde skeleton.1

During the synthesis of sacrolide A, attempted deprotection of (1) gave the desired product (2) along with an unexpected contaminant (3) in substantial amounts. Formation of (3) was speculated to be the result of E/Z isomerization of the conjugated double bond and subsequent cyclic hemiacetal formation followed by dehydration (Scheme 1).2

Scheme 1

Chloromethyl methyl sulfide/KI catalyses desilylation and acetal formation. The reaction also works with a combination of (ethylthio)methanol and TBDMSCl or TMSCl, but fails when only (ethylthio)methanol is used. On the basis of this information, and reactivity trends of aldehydes (electron-deficient aldehydes react faster), it is proposed that the active catalyst is methylene sulfonium halide (4), which activates the aldehyde and converts the OH group on the aldehyde into a better leaving group (Scheme 2).3

Scheme 2

Acetal configuration interconversion is observed by 1H NMR spectroscopy for the six-membered ring phenyl-substituted acetal during its formation from the corresponding diol. These diastereomers are hypothesized to interconvert as a result of acid catalysis under the reaction conditions.4

A gold(I)-catalysed ring opening of cyclic acetals and ketals by trimethylsilyl alkynes was achieved, which exploits the use of gold(I)-silicon catalysis. The reaction benefits from in situ and simultaneous generation of small amounts of a silicon-based super acid and a gold alkynylide. The Lewis acid activates the electrophilic cyclic acetal or the ketal, while the in situ formed gold alkynylide, which is more nucleophilic than the parent alkynylsilane, attacks the acetal.5

Removal of the acetonide group from (5) does not result in the formation of expected product (6), and instead (7) is formed.6 A plausible mechanism involves an acid-catalysed ring opening of acetonide via deprotonation. Finally, the acid-catalysed removal of hemiketal provides (7) (Scheme 3).

Scheme 3

Substituted enaminoesters and acetal groups undergo an intramolecular cyclization with Lewis acids. The reaction probably undergoes a [1,5]-hydride shift after activation of the alkene by the Lewis acid. The zwitterionic intermediate undergoes the cyclization process, providing spirocycles. Density function theory calculations were performed to validate the proposed mechanism. Partial racemization observed in the process is explained using density functional theory (DFT) calculations.7

Reactions of Glucosides

Two isomeric glucosides hydrolyse at rates differing by 106-fold, despite the fact that they both give the same hydrolysed products (Scheme 4). Experimental and quantum chemical calculations revealed that ground-state destabilization and transition-state stabilizing effects are responsible for the observed reactivity differences. The ground-state destabilization in (8) is due to a longer glycosidic bond length because of a negative inductive effect of the proximal chlorine atom. Compared to (9), the transition state for the hydrolysis of (8) has better stabilization of the charge at the leaving group oxygen due to the presence of proximal chlorines.8

Scheme 4

A Pd-catalysed decarboxylative Wittig reaction furnishes c-vinyl glycosides diastereoselectively. The Tsuji-Trost reaction, followed by the Wittig reaction, is the proposed reaction pathway. For non-pyridyl groups, Z-selectivity is observed as the oxaphosphetane is formed via the Newman projection (10), which allows for minimal gauche interactions between the sugar moiety and the aldehydic substituent (Scheme 5). The E-selectivity of the pyridyl group is a result of PdM coordination that brings the P-ylide and aldehyde into close proximity, overcoming the opposing steric factors.9

Scheme 5

Sugars are introduced at the C3, C5, and C11 positions of macrolactones in a regiodivergent manner by selecting an appropriate chiral phosphoric acid catalyst or through the introduction of stoichiometric boronic acid-base additives. Mechanistic studies suggest that the reactive intermediates involved in the reaction are covalently linked anomeric phosphates rather than oxocarbenium ion pairs.10

Glycosylation of 4,6-tethered glucosides with a panel of nucleophiles reveals that decreasing electron density on glucosides or increasing electron density of nucleophilic atoms results in increasing ß-selectivity. It is proposed that when the glucoside is electron deficient and the nucleophile is strong, ß-selectivity occurs because the ß-triflate is in equilibrium with the a-triflate which is less stable, leading to ß-products. When the nucleophile is weak and the glucoside is electron rich, the triflate dissociates to form an oxocarbenium species. Nucleophilic attack from the bottom face leads to a-products through a chair-like transition state.11

Reactions of Ketenes

DFT calculations have been performed at the B3LYP/6-311+G(d,p) and M)6-2X/6-31(d,p) levels to understand the experimental outcome of the reaction between hydrazone (11) and a-oxo-ketene (12) (Scheme 6). Among the three possible pathways, leading to different products, the 1,3-dipolar cycloaddition is the most favoured. The mechanism is speculated to involve a 1,2-hydrogen shift that proceeds via quantum mechanical tunnelling. Without this 1,2-hydrogen shift, the other two Diels-Alder product pathways are expected to be favoured.12

Scheme 6

The 3?+?2-cycloaddition between nitrones and ketenes has been studied using DFT and molecular electron density (MEDT). The reaction takes place in one kinetic step, but in a non-concerted mechanism. The study predicts a switch to a two-step mechanism with electrophilic ketenes.13

DFT methods have been used to understand the mechanism and stereochemical outcome of trimethylsilylquinine (TMSQ) or methylquinidine (MeQd)-catalysed 2?+?2-cycloaddition between methylketene (MK) and methylphenylketene (MPK). With TMSQ, R-E isomer is predominantly formed, while with MeQd, S-Z isomer is the major product. Formation of lactone occurs via a stepwise process. The enantio- and...