Pivalaldehyde

[630-19-3]  · C5H10O  · Pivalaldehyde  · (MW 86.15)

(sterically demanding electrophile;1 coreagent in molecular oxygen oxidations; production of reagents for enantioselective synthesis2)

Alternate Names: 2,2-dimethylpropanal; trimethylacetaldehyde.

Physical Data: mp 6 °C; bp 77-78 °C; d 0.793 g cm-3.

Solubility: sol alcohol, ether.

Form Supplied in: colorless liquid.

Preparative Methods: the most accepted preparative method is the reaction of t-Butylmagnesium Chloride with Methyl Formate.3 Recently, the use of N,N-Dimethylformamide as the formylating reagent has been studied,4 as well as the direct reaction of t-Butyllithium with Carbon Dioxide and metal hydrides.5

Sterically Demanding Electrophile.

The unique structural characteristics of this reagent include the most sterically demanding, and highly symmetric, simple alkyl group1 adjacent to a reactive electrophilic center, and the absence of acidic protons on the carbon atom adjacent to the carbonyl functionality. These attributes have made pivalaldehyde a standard reagent in the study of carbanion reactivity, with intensified use in the more recent era of stereoselective synthesis. Thus the oxonium ion generated from pivalaldehyde reacts with the expected high degree of stereoselectivity (eq 1).6 Likewise, in the reaction of boron enolates derived from a-carbonyl radicals (eq 2),7 pivalaldehyde consistently affords the highest erythro:threo selectivity (0:100) with no loss of chemical yield compared to other aldehydes.

However, there are numerous examples in the literature to indicate that the steric bulk of the t-butyl group can severely deactivate the electrophilicity of the aldehyde functionality, resulting in drastically reduced yields. The suggestion that pivalaldehyde is a nonchelating aldehyde, and therefore a poor participant in reactions which progress through chelation of the electrophile prior to C-C bond formation, seems to be reasonable given the experimental results. The reactions of this aldehyde with the lithium anions of amides (eq 3)8 and esters,9 the intermolecular pinacol cross-coupling reaction using vanadium(II) reagents (eq 4),10 and the addition of vinylzinc reagents (eq 5)11 all suffer severely reduced yields and, in the latter case, significantly reduced stereoselectivity in the C-C bond forming event.

Coreagent in Molecular Oxygen Oxidations.

Pivalaldehyde has been shown to be one of several aldehydes that function as effective reductants in the oxidation of alkenes to epoxides by molecular oxygen. In the process, which is most often metal catalyzed, the aldehyde is oxidized to the corresponding carboxylic acid. At least two different mechanisms appear to be operating. In the nickel(II)-catalyzed case,12,13 the oxidation occurs through a singlet oxygen-type species.14 The reaction is characterized by the loss of stereochemistry in the oxidation of both cis- and trans-2-butene.13 In addition, the epoxidation of cholesteryl benzoate affords a 31:69 mixture of stereoisomers, with the b-isomer as the major component. This result is opposite to those from more traditional expoxidation reagents (m-Chloroperbenzoic Acid, MMPP), which afford the a-epoxide as the major product. Pivalaldehyde is not an effective reductant in the nickel(II)-catalyzed Baeyer-Villiger oxidation of ketones,15 but is the most effective aldehyde in the manganese(III)-catalyzed enantioselective epoxidation of 1,2-dihydronaphthalene by oxygen in the presence of various enantiomerically pure salen ligands (eq 6).16 Similar results have been obtained by Jacobsen17,18 and Katsuki19 using Iodosylbenzene or Sodium Hypochlorite as oxidant.

Epoxidations can also be effected without the use of metal catalysts.20 In this case it appears as if peroxy acids (formed by oxygen interacting with pivalaldehyde) are the ultimate oxidizing agent. Pivalaldehyde is the most effective aldehyde of those studied in this reaction, which show the usual profile of reactivity and selectivity expected for a peroxy acid oxidation (eq 7).

Reagents for Enantioselective Synthesis.

A large body of work has been accumulated since the mid-1980s which employs the t-butyl group of pivalaldehyde as a sterically demanding presence for enantioselective synthesis. The transformation of 4-hydroxyproline to a-methyl-4-hydroxyproline (eq 8)21,22 in enantiomerically pure form presents both the concept and practice of the self-reproduction of chirality23 technique, in which substituted a-amino acids are obtained without the use of external chiral auxiliaries. Pivalaldehyde has been employed almost exclusively in the cyclization event, with a small amount of work having been done with benzaldehyde.

Analogous transformations have been performed on heterocycles prepared from alanine,24-26 valine,24,25 methionine,24,25 cysteine,27 phenylglycine,24 phenylalanine,24,25 aspartic acid,28 glutamic acid,28 serine,29-31 and 2-azetidinecarboxylic acid.32 The list is not exhaustive. All have involved the formation of five-membered N,O- (oxazolidinone) or N,N-acetals (imidazolidinone), or both, from cyclization with pivalaldehyde. The N,N-acetals arise from cyclization of the corresponding amino acid N-methylamide. Diastereoselection in the cyclization event varies from 0 to 100%. Reactions of the heterocyclic anions with other alkylating reagents (beyond methyl iodide), aldehydes, ketones, heteroelectrophiles, and Michael acceptors are described. Dipeptide derivatives have also been synthesized.33 A complete discussion of the structures of the heterocycles and the factors controlling the diastereoselectivity of the anion reactions has been published.34 It is argued that in certain cases the high diastereoselectivity is not a direct result of steric effects dictated by the t-butyl substituent. Rather, it arises from torsional effects exemplified by significant pyramidalization at the trigonal centers in the molecules.35

A more general approach to amino acids begins from the corresponding cyclized glycine heterocycle. The enantiomers of the imidazolidinone have been prepared from the degradation of other amino acids,36 resolution of the racemic mixture with mandelic acids,37 and by asymmetric synthesis employing a-methylbenzylamine.38 The corresponding oxazolidinone can be chromatographically resolved.39 The imidazolidinone can function as both a nucleophilic (eq 9) and electrophilic glycine equivalent (eq 10),40 similar to molecules developed by other researchers,41 while the products from oxazolidinone nucleophile reactions are claimed to be more easily isolated.42

The utility of these chiral building blocks is extended by the formation of unsaturated derivatives. Cyclic dehydroalanine molecules43 function as radical44 and nucleophile45 acceptors (eq 11). Internal alkenes are prepared46,47 and reacted48-50 with a wide variety of reagents, offering additional entries into enantiomerically pure compounds with chirality centers bearing oxygen, nitrogen, and/or sulfur.

More recent work has focused on b-amino acid synthesis through pyrimidinone structures, again prepared by this reagent in a cyclization reaction. Enantiomerically pure dihydro- and perhydropyrimidinones can be obtained directly from asparagine51,52 or 3-aminobutanoic acid.53 Alternatively, racemic perhydropyrimidinones arise from b-alanine,54 and the enantiomers have been separated by chromatographic resolution.39 These compounds all exhibit axial t-butyl groups,34,55 and selectivity is dictated by steric effects. An unusual palladium-catalyzed arylation reaction leads to b-aryl-b-amino acids in enantiomerically pure form (eq 12). A mechanism has been presented.55

Parallel strategies have been developed with dioxolanones,56 dioxoanones, and dioxinones57,58 (O,O-acetals), leading to a variety of enantiomerically pure oxygen-containing products via the pivalaldehyde-derived stereogenic center. While a wide variety of b-hydroxy carboxylic acids have been employed as starting materials,59,60 the bulk of the work has been performed on dioxanones and derivatives originating from (R)- or (S)-b-hydroxybutyric acid. As in the case of the N,O-acetals, diastereoselectivity in the cyclization event is quite variable, with best success in the formation of bicyclic structures.60 Transacetalization with mild acid appears promising.61 Although the t-butyl substituent on the six-membered ring heterocycles is in an equatorial environment, these systems nonetheless exhibit high stereocontrol in many different reactions. It has been suggested that torsional effects are responsible.62 Other explanations have been made.63 Both nucleophilic (enolates and dienolates64) and electrophilic (bromides65 and both endo-66 and exocyclic67 enoates) six-membered ring heterocycles have been prepared and reacted to afford a wide range of products. An interesting example is the production of chiral tris(hydroxymethyl)methane derivatives (eq 13).68

Dioxolanones derived from pivalaldehyde cyclization have been employed in Diels-Alder reactions as captodative dienophiles.69-71 The corresponding heterocycle with a cyclohexanecarbaldehyde-generated stereogenic center gives somewhat inferior diastereoselectivity in the formation of exo cycloaddition products.72


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Joseph P. Konopelski

University of California, Santa Cruz, CA, USA



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