Nucleophilic addition to acetals and

Nucleophilic Addition to Acetals and Hemiacetals—C2 Functionalization of Lactol... 

In chapter entitled Synthesis of Substituted Tetrahydrofurans, J. D. Rainier outlines the advances that have been made during the last 10 years in the synthesis of tetrahydrofurans such as nucleophilic additions to acetals and hemiacetals, cycloadditions, oxidative cyclizations, furan reductions, Prins-pinacol cascades, ring-opening of bicyclic substrates, and nucleophilic substitutions. 

Introduction. Ti-TADDOLates are a,a,a, a -tetraaryl-2,2-disubstituted l,3-dioxolane-4,5-dimethanolatotitanium derivatives. The most common substituents are R, R = Me/Me and Ph/Me, Ar=Ph and 2-naphthyl, X, Y = C1/C1, t-PrO/Cl, Cp/Cl, and i-PrO/i-PtO. The corresponding TADDOLs (2) are available in both enantiomeric forms from tartrate esters which are acetalized (R R CO) and allowed to react with aryl Grignard reagents. The reactions performed in the presence of Ti-TADDOLates or with Ti-TADDOLate derivatives include nucleophilic additions to aldehydes - - and nitroalkenes of alkyl, aryl, and allylic - groups aldol additions hydrophosphonylations and cyanohydrin reactions of aldehydes inter- and intramolecular Diels-Alder additions ... 

The aUyl moiety of allylic acetate undergoes nucleophilic addition to aldehydes and provides homoallyl alcohols in good to moderate yield in the presence of 2 mol % of PdCl2(PhCN)2 and 3 equiv of tin(ll) dichloride in DM1 (l,3-dimethyl-2-imidazolidinone) at 25-60 °C (Scheme The reaction displays high chemoselectivity and the aldehyde moiety of 10-oxoundecanal is selectively aUylated under the conditions shown in Scheme 5. 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

Unsaturated Hydrocarbons. Olefins from ethylene through octene have been converted into esters via acid-catalyzed nucleophilic addition. With ethylene and propjiene, only a single ester is produced using acetic acid, ethyl acetate and isopropyl acetate, respectively. With the butylenes, two products are possible j -butyl esters result from 1- and 2-butylenes, whereas tert-huty esters are obtained from isobutjiene. The C5 olefins give rise to three j iC-amyl esters and one /-amyl ester. As the carbon chain is lengthened, the reactivity of the olefin with organic acids increases. 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

The development of methods to effect nucleophilic addition to carbon-carbon double bonds by prior activation with metal cations has been applied, at least in a preliminary way, as a method of pyrrole ring closure. The conversion of butadienes to N-substituted pyrroles can be accomplished in two stages. In acetic add, 1,4-dienes react with PdnCl2 to give tr-allyl complexes with introduction of acetate at C-4. The ir-allyl complexes then react with amines to give a l-amino-4-acetoxy-2-butene (equation 70). When the addition of the amine is carried out in the presence of a silver salt and triphenylphosphine, a pyrrole is isolated, probably by cyclization of the amino-substituted allyl-Pd complex (equation 71) (81CC59). Although this procedure is attractive in terms of the simplicity of the... 

Nucleophilic addition to the neutral activated acyl group is a favored process, and coenzyme A is a good leaving group from the tetrahedral intermediate. The occurrence of this process with the acetate anion, that is, acetate reacting with an enolate anion, again provides a sharp contrast with the... 

Nucleophilic addition to ir-allylpalladium complexes is known to take place widi a range of nucleophiles. and die mechanism and steieochonistry of diese reactions have been thoroughly investigated over die last few years. - For example, reaction with acetate anion occuis in the presence of benzoqui-none at room temperature in acetic acid solution by initial cis attack at the metal atom and subsequent migration. Alternatively, in die presence of chloride ions, a trans attack takes place to give the pr uct of opposite stereochemistry (Scheme 10). Intramolecular versions of the reaction are known. ... 

In nucleophilic catalysis the catalytic properties are a result of the intermediate formation of a 1-acylimidazole (Scheme 27). When the ester has a good leaving group, e.g. p-nitrophenyl acetate, the effective catalyst is the imidazole neutral molecule which increases in effectiveness as the basic pKa of the heterocycle increases. Where, however, the ester has a poor leaving group, e.g. p-cresol acetate, the imidazole anion becomes involved and general base catalysis predominates. Thus, for imidazoles with pjK"a 4 catalysis by the anion is the main reaction. Imidazole is a much more effective nucleophile than other amines in this type of reaction since it is a tertiary amine with little steric hindrance, and it is able to delocalize the positive charge which results from the nucleophilic addition to... 

Protected (5)-ethyl lactate cleanly acylates methyllithium to afford the 2-butanone with essentially complete enantiomeric fidelity and in nearly quantitative yield. Various diastereoselective constructions were achieved by nucleophilic addition to the ketone (eq 5). For example, addition of vinyllithiums, followed by acetal formation and Lewis acid-mediated rearrangement, provided a ready entry into the indicated 3-acyltetrahydrofurans. 

Nucleophilic addition to carbonyl functionalities undoubtedly represents one of the most important reactions of Grignard reagents. One such reaction is the alkylation of carbon dioxide to give carboxylic acid derivatives. Analogous reactivity is also observed between [TpBu jMgCH3 and CO2. which gives the acetate derivative [Tp ]Mg(f/ -02CCH3) [Eq (6)]. 

Acetal formation thus involves (a) nucleophilic addition to a carbonyl group, and (b) ether formation via a carbonium ion. 

Chiral acetals can be used as auxiliaries in the diastereoselective reactions of Grignard reagents with acyclic as well as cyclic a-keto acetals. Nucleophilic addition to the monoprotected diketone (69 equation 18) occurs with excellent stereoselectivity to generate the corresponding tertiary alcohol (70) as the major product, usually with greater than 95 5 selectivity. Removal of the ketal yields a-hydroxy ketones of high optical purity. In most examples, enantiomeric excesses of 95% and higher are observed in the resultant keto alcohols. Table 17 represents the results of additions to cyclic and acyclic substrates. 

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