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Reactions of Aldehydes and Ketones and their Derivatives

B. A. Murray

Department of Science, Technological University of Dublin (TU Dublin), Dublin, Ireland

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
  • Other 'Name' Reactions of Imines
  • Stereoselective Hydrogenation of Imines, and other Reductive Processes
  • Cyclizations of Imines
  • Other Reactions of Imines
  • Oximes, Oxime Ethers, and Oxime Esters
  • Hydrazones and Related Species
• C-C Bond Formation and Fission: Aldol and Related Reactions
  • The Asymmetric Aldol
  • The Mukaiyama Aldol
  • The Morita-Baylis-Hilman Reaction, and its Aza-variants
  • Other Aldol and Aldol-type Reactions
  • The Michael Addition
• Other Addition and Related Reactions
  • The Wittig and other Olefinations
  • Miscellaneous Additions
• Reactions of Enolates and Related Reactions
• Oxidation of Carbonyl Compounds
  • Cross-Dehydrogenative and Related C-C Coupling Processes, and C()-H Activations
  • Other Oxidative Processes
• Reduction of Carbonyl Compounds
• Miscellaneous Cyclizations
• Other Reactions
• References

Formation and Reactions of Acetals and Related Species

Tetrahydropyran acetals [(1), both cis- and trans-isomers] undergo rhodium(II)-catalyzed intramolecular C-H insertions of the proximal diazoketone to give spirocyclic orthoesters (2a/2b) (Scheme 1).1 There are anomalous C-O bond-forming insertions, but no trace of the expected C-C product was observed. DFT has been used to explore the factors behind this unusual selectivity, with C-O bond formation being calculated to be favoured by ca. 3 kcal mol-1.

Scheme 1

Dihydrolevoglucosenone [(3), cyrene] incorporates the 6,8-dioxabicyclo[3.2.1]octane structure found in several natural products. It undergoes highly diastereoselective aldol condensation with aromatic aldehydes [(4); X = CH, R = various 3/4/5-substituents or H] to give exocyclic enones (5). With an ortho-phenolic benzaldehyde [(4) with X = C-OH], further reaction gives a tetracyclic derivative (6) with adjacent cyclic acetal and cyclic hemiketal functionality, with the carbon being chiral in both cases. 2-Pyridinecarboxaldehyde [(4), X = N] undergoes many additional steps to exclusively give an unexpected spironolactone (7) bearing two pendant pyridines (Scheme 2). Mechanisms are discussed in all cases.2

Scheme 2

A urea with a pendant acetal (8) has been reacted with nucleophilic aromatics to give a range of heterocyclic products. The acid-catalyzed reaction has a complex mechanistic manifold, with the nature of the product dependent on the nucleophilicity of the arene and the strength of the acid. Possible products included arylpyrrolidines, bispyrroles, or pyrrolidinequinazolines.3

Phthalane (1,3-dihydro-2-benzofuran) frequently occurs at the core of natural products and drugs. A range of 1-alkylidenephthalanes (9), some bearing additional functionality in substituent R4, have been prepared from the corresponding ortho-bromophenyl-alkyne-acetal (10) (Scheme 3), with good deals of predominantly (Z)-(9).4

5-Hydroxyfurfural (11) is a potentially valuable biofeedstock, but its use is hampered by formation of solid humin by-product during its processing. Now conversion to a cyclic acetal [(12),

Scheme 3

using 1,3-propanediol] sets up a clean aerobic oxidation to give furan-2,5-dicarboxylic acid (13) in up to 95% yield, using a gold/CeO2 catalyst in water at 140?°C/5?atm (Scheme 4). Kinetic studies and DFT calculations support partial hydrolysis of (12) and subsequent oxidative dehydrogenation of the in situ-generated hemiacetal.5

Scheme 4

The kinetics and mechanism of the formation of the diethyl acetal of furfural (furan-2-carboxaldehyde) have been studied with Ni-Al-layered double-hydroxide catalysts; the nitrate form was efficient via Lewis acid sites, while the carbonate form was not. Calculations probed the relative contribution of Lewis and Bronsted acid sites.6

Cs2.5, a heteropoly acid of formula Cs2.5H0.5PW12O40, catalyzes acetalization of glycerol with acetone and also with formaldehyde. For acetone, the five-membered cyclic product, solketal, was favoured 98:2 over the six-membered isomer.7

The reductive Hosomi-Sakurai reaction of acetals, R1-CH2-CH(OR2)2, with allylsilanes, TMS-CH2-C(R3)=CH2, to give alcohols has been carried out as a chemo-, regio-, and diastereo-selective process. As an internal hydrogenation not requiring hydrogenolytic conditions, it is quite tolerant of functional groups. Key to the mechanism is a carbocation (formed by protonation of a homoallylic ether) undergoing a 1,5-hydride transfer. If this cation is sufficiently stabilized, the hydride transfer becomes rate-determining. Consistent with this suggestion, a series of aryl-substituted allylsilanes (R3 = Ar) show evidence of such a mechanistic switch, as shown by an abrupt break in the Hammett plot of the de.8

Nanoporous aluminosilicates catalyze direct aldols of acyclic acetals with 1,3-dicarbonyls rather than giving the expected Knoevenagel eliminations.9

Frustrated Lewis Pair (FLP) catalysis has been applied to polymerization of renewable cyclic acrylic monomers using silyl ketene acetals and tris(pentafluorophenyl)boron.10

A series of bicyclic acetals with a variety of environments-fully saturated, one ring aromatic, or one oxygen part of an enol ether-have undergone chemoselective formation of oxocarbenium ions, depending on hybridization type: sp3 versus sp2, with the latter either aromatic or vinylic. Highly efficient synthesis of a range of heterocyclic systems results, with yields/de/ee up to 93/95/99%.11

Indoles have been converted to carbazoles, using a three-component reaction; an a-bromoacetaldehyde acetal performs a Friedel-Crafts-type alkylation of the indole [catalyzed by bismuth(III)] with subsequent [4 + 2] annulation with a ketone.12

a-Oxo-ketene N,N-acetals [(14), X = O] undergo formal oxidative C-C bond cleavage and subsequent cyclization to give isoxazolines [(15), X = O] using PIDA [phenyliodine(III) diacetate] as oxidant. The corresponding thioxo substrates [(14), X = S] give isothiazoline derivatives [(15), X = S]. In the oxygen case, the product easily undergoes Baldwin rearrangement to the 2-imino-1,3-oxazoline isomer (16), which can be hydrolyzed in acid to the corresponding oxazolone (17) (Scheme 5).13

Scheme 5

Many studies suggest that trimethylenemethane (TMM, C4H6) has a ground-state triplet structure (18), together with a low-lying excited singlet state. A DFT study has looked at the generation of TMM structures by ring-opening of dialkoxymethylenecyclopropanes and methylcyclopropane-thioacetals [(19), X = O, S] (Scheme 6). A range of resulting ketene-forming reactants and cyclizations are also reported.14

Scheme 6

Fluorinated benzofurans (20) have been prepared from polyfluorophenols (21), using ketene dithioacetal monoxides (22), the latter being activated by an acid anhydride (Scheme 7). The sigmatropic de-aromatization/de-fluorination strategy uses (i) an interrupted Pummerer reaction followed by [3,3] sigmatropic rearrangement, (ii) zinc-mediated defluorination, and then (iii) acid-promoted cyclization/aromatization. The 2-methylsulfanyl moiety in the products (20) facilitates further functionalization.15

Scheme 7

Functionalized tetrasubstituted thiophenes (23) have been prepared one-pot from ketones (R1-CH2COR2), isothiocyanates (R3-CNS), and 2-picolyl bromide using potassium carbonate as base in DMF at 60?°C. Sulfur ylide-like intermediates, with stabilization by pyridine, are proposed and supported by 1H-NMR data. A number of five-membered aromatic heterocyclic moieties can replace the 2-pyridyl substituent.16

Alkylthio-functionalized enaminones (24, a-oxo ketene N,S-acetals) have been converted to unsaturated amides (25) (Scheme 8) under mild conditions in a metal- and CO-free process involving vicinal alkylthio migration.17

Scheme 8

For carbohydrate-derived lactone acetals undergoing a vinyl Grignard process, see The Wittig...