CHAPTER 1
Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray

Department of Science, Dublin, Ireland

1. Formation and Reactions of Acetals and Related Species
2. Reactions of Glucosides
3. Reactions of Ketenes
4. Formation and Reactions of Nitrogen Derivatives
   1. Imines: Synthesis, and General and Iminium Chemistry
   2. Mannich, Mannich-type, and Nitro-Mannich Reactions
   3. Other 'Name' Reactions of Imines
   4. Synthesis of Azacyclopropanes and Azirines
   5. Alkylations, Arylations, Allylations, and Additions of Other C-Nucleophiles
   6. Miscellaneous Additions to Imines
   7. Oxidation and Reduction of Imines
   8. Other Reactions of Imines
   9. Oximes, 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. Asymmetric Aldols
   3. The Mukaiyama Aldol
   4. The Baylis-Hillman Reaction and its Morita Variant
   5. Other Aldol and Aldol-type Reactions
   6. Allylation and Related Reactions
   7. Alkynylations
   8. The Stetter and Benzoin Reactions
   9. Michael Addition and Miscellaneous Condensations
6. Other Addition Reactions
   1. Addition of Organozincs
   2. Arylations
   3. Addition of Other Organometallics, Including Grignards
   4. The Wittig, Julia-Kocienski, Peterson, and other Olefinations
   5. Hydrosilylation, Hydrophosphonylation, Hydroboration, and Addition of Isocyanide
   6. Miscellaneous Additions
7. Enolization, Reactions of Enolates, and Related Reactions
8. Oxidation and Reduction of Carbonyl Compounds
   1. Oxidation of Aldehydes to Acids
   2. Oxidation of Aldehydes to Amides, Esters, and Nitriles
   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

Lutetium(III) triflate catalyses acetalization of acetone with glycerol, (HOCH2)2-CH(OH), giving a regioselective preference for the 1,3-dioxolane product (1, 'solketal'), as against the six-membered-ring 1,3-dioxane alternative. Density functional theory () studies have identified a constrained hemiacetal intermediate to explain the selectivity.(1)

To assist in using glycerol by-product from biodiesel manufacturing, a quantum mechanics () study of its acetalization with acetone has been undertaken, using benzenesulfonic acid as catalyst.(2)

Nucleophilic substitutions of acetals such as (2) with a remote benzyloxy group can be highly diastereoselective, an effect which increases as the reactivity of the nucleophile is increased, in violation of the reactivity/selectivity principle. The result has been explained in terms of multiple conformers of a reactive intermediate leading to the product.(3)

Acetophenones undergo mild one-step a-haloacetalization in ethylene glycol, using 1,3-dihalo-5,5-dimethylhydantoins (3; X?=?Cl or Br). Temperature and solvent effects have been investigated.(4)

A kinetic study of acetal hydrolysis has examined the effect of 4-alkoxy groups, with appropriate control of stereochemistry. For example, several acetal series (4) have been prepared with varying ring size (n?=?1-4), and either endocyclic oxygen (X?=?H, Y?=?O) or exocyclic (X?=?OBn, Y?=?CH2), with appropriate non-cyclic controls such as 4-benzyloxy-butanal dimethylacetal. Hydrolysis rate enhancements are of the order of 20-fold, perhaps 200-fold when controlled for inductive destabilization. However, rates of solvolysis of related tosylates show much larger effects, including a factor of nearly

106 going from five- to eight-membered rings. It is concluded that neighbouring-group participation operates in the tosylate solvolysis, but not in the acetal hydrolysis.(5)

Using an amine as a nucleophile carrier, R2N-CH2Nu, a range of progressively more hindered a-cyanoamines, R2N-CH2-C?N (R?=?Me, Et, i-Pr, and CyHx), have been tested as cyanating agents of acetals. The congested dicyclohexyl compound proved best: using 2?equiv, together with 2 equiv of trichlorosilane triflate in DCM at 0?°C for 30?min, benzaldehyde dimethyl acetal gave 95% yield of PhCH(OMe)CN. Similar results were obtained for a wide range of acetal types, and indeed for orthoesters (to give the cyanoacetal). Investigation by nuclear magnetic resonance () spectroscopy helped identify an oxocarbenium ion intermediate, Ph-CH?O+-Me (as the triflate), upon addition of Cl3SiOTf, and addition of (CyHx)2N-CH2-C?N rapidly gave the product, together with an iminium cation, (CyHx)2N+ ?CH2.(6)

Regioselective monoalkylation of diols is often achieved via dialkylstannylene acetal intermediates. Though slow to form, addition of nucleophiles helps, especially fluoride. The reaction of a fluoride salt (5) with bromomethane has now been studied at several levels of theory in the gas phase, and in DMF solution. In solution state most closely related to experiment, fluorinated monomers and monofluorinated dimers showed similar activation energies. A widely considered 'Sn-O bond cleavage first' mechanism did not feature, with C-O bond formation actually well advanced over Sn-O cleavage in the TS. Comparing gas phase with DMF, solvation effects significantly lower the energy of fluoride ion to form (5), but the tetramethylammonium cation stays close to the F atom.(7)

A series of dialkyl acetals, Me2N-CH(OR)2, derived from DMF have been screened for their ability to N-alkylate 8-oxoadenosine and guanosine at N(7). Comparative kinetic experiments have been used to explore the mechanism and side-reaction possibilities.(8)

ortho-Alkynylbenzaldehyde acetals and thioacetals (6) undergo a range of divergent cyclizations catalysed by palladium(II) or platinum(II) halides. While metal-triggered C-X cleavage was previously proposed, DFT calculations now point to electrophilic activation of the alkyne as the initiating step. Terminal and non-terminal alkyne cases are contrasted, and the nature of the heteroatom's effect on the route taken was also studied. The DFT results have led to some literature assignments being challenged, with new experiments reported that validate the new assignments.(9)

Hemithioacetal enantiomers (7) contain an unstable quaternary chiral centre and can equilibrate through their open-chain ketone-enethiol form (8). Variable temperature and exchange spectroscopy () NMR techniques have been used to measure the rates and barriers for the interconversion, in toluene solvent. A DFT study was also undertaken, but the toluene solvent severely constrains the possibilities in terms of acid-base and hydrogen-bonding chemistry. A computed barrier of 40?kcal?mol-1 is at odds with half that found by NMR. But an alternative path was found to resolve the discrepancy: a 'solvent molecule' is available . in the form of another hemithioacetal, which - through a dimer complex - assists the proton transfers.(10)

'Fmox', a 3-Fmoc-(1,3)-oxazinane moiety, has been developed as a base-labile aldehyde-protecting group. For the example of the doubly protected 3-aminopropanal (9), deprotection is 100% effected with 1% piperidine in 2?h, while leaving the amine protection intact. The group, like many others, is acid-labile to the extent of 6% in 20% acetic acid and 93% in 10% TFA, though it survives in 0.1% TFA for 10?min. Protection of the aldehyde (10) requires N-Fmoc-3-amino-propanol/Na2SO4/HCl(cat.)/50?°C.(11)

Enantiomerically enriched ß 2-amino acids have been accessed in the form of their N,N-diprotected esters (11) via dual activation of an enal (trans-R-CH?CH-CHO) and an N,O-acetal (Bn2N-CH2-OMe), the activations being achieved by an N-heterocyclic carbene () and an in situ-generated Brønsted acid, respectively. The enal is converted to an azolium enolate, and the acetal to an iminium ion (Bn2N+ ?CH2) and methanol. Typical conditions are mild base at ambient temperature, giving...