Alkylation Pivaldehyde

Redistilled N, O-persilylated L-proline 438 reacts with pivaldehyde in pentane at ambient temperature to give the 0,N-acetal 439 in 78% yield in the presence of LDA this condenses, a to the carbonyl group, with N-alkyl-2-pyrrole aldehydes [48] (Scheme 5.14). 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

Pyrazolopyrimidine 148 reacted with magnesium to yield the corresponding Grignard reagent 149 that reacted with pivaldehyde to yield the corresponding C-alkylated derivative 150 (Scheme 5) <2003JOC2054>. 

Pivaldehyde, (CH3)3CCHO (1), Mol. wt. 86.13, m.p. 6°. Supplier Aldrich, Fluka. a-Alkylation of amino acids.12 The N-methyl amide (2) of an a-amino acid... 

Reaction of the proline derivative 8 with pivaldehyde (1) in CH2C12 catalyzed by TFA results in a single product (9). Treatment of 9 with MeLi and then with LDA furnishes the enolate a. Alkylation or reaction with aldehydes or acetone followed by acid hydrolysis furnishes enantiomerically pure 2-substituted 4-hy-droxyprolines (10), with retention of configuration.3... 

Asymmetric alkylation andaldol condensations.2 The enolate (2) of 1 reacts with primary iodides to give essentially a single product (3), in which the alkyl group is syn to the cyclopentadieny ring. Aldol condensation with acetone leads to only one observable product (4). Only two isomeric products are obtained on aldol condensation with prochiral aldehydes and ketones as expected for a rranx-enolate, the i/ww-aldol predominates or is the exclusive product (5) as in the case of pivaldehyde. 

It is often very useful to be able to alkylate a readily available chiral a-hetero-substitut-ed carboxylic acid in an enantiospecific manner, as a means of using the chiral center and at the same time building-up the rest of the target carbon skeleton. Such a reaction has been devised by Seebach and coworkers524. In this process a-hydroxy- and a-mercaptocar-boxylic acids were first reacted with pivaldehyde, to produce a 1,3-dioxolanone or 1,3-oxathiolanone. This was followed by reaction with base and alkylation by an alkyl halide and subsequent hydrolysis to regenerate the hydroxyl or mercapto group (equation 70). The product was obtained in greater than 95% ee. Similar reactions with other electrophiles were also successful. 

The ester precursors of the enolates (114) and (116) were prepared from reactions of glyceric acid or serine with pivaldehyde. After alkylation, the parent alkylated acids were recovered by hydrolysis. See-bach and coworkers, who have pioneered this type of procedure, have called it self-reproduction of chir-... 

Probably the most important and useful of all these amino acid-based chiral enolates are those of Seebach.7 The simplest is made from proline 17 simply by forming the iV, O-acetal 66 with pivaldehyde (f-BuCHO). The lithium enolate 67 is alkylated diastereoselectively with various electrophiles E+ to give one diastereoisomer of 68. 

An as yet unexplicable drawback of the described catalytic system (S,S)-5/pivaldehyde/dioxygen is its limitation to 2-aryl substituted cyclohexanones the positional isomer 4-phenylcyclohexanone or 2-alkyl substituted cyclohexanones are not converted. The strained cyclobutanones, however, will almost always react under the catalytic conditions. Thus, the racemic bicyclic cyclobu-... 

Monocyclic cyclobutanones 9 (Fig. 1) with alkyl, aryl, or carboxylato substituents at C3 gave under the usual catalytic conditions optically active lactones with only moderate enantiomeric excesses (up to 47% ee) [25]. Increasing the amount of pivaldehyde used in the catalysis led to higher yields without a significant decline in enantioselectivity. For instance, 3-phenylcyclobutanone (9, R= Ph) was converted to the corresponding (S)-lactone in 66% yield with either... 

Intraligand asymmetric induction. An instructive introduction to intraannular alkylations is the self-regeneration of chirality centers concept introduced by Seebach [62-66]. Scheme 3.9 illustrates the concept and Table 3.1 lists several representative examples. A chiral educt, such as an amino acid derivative, is condensed with pivaldehyde. This derivatization creates a new stereocenter selectively, and this second stereocenter then controls the selectivity of the subsequent alkylation by directing the electrophile to the face of the enolate opposite the tert-butyl group, a good example of intraannular 1,3-asymmetric induction. After purification of the alkylation product, hydrolysis affords enantiomerically pure products. 

Incorporation of an auxiliary into a cyclic system has been used for the diastereoselective addition of cuprates to unsaturated 6-membered ring dioxinones, which are perhaps less important for their synthetic potential than for the mechanistic insight they provide. The dioxinones shown in Scheme 4.12a were obtained from / -3-hydroxybutanoic acid using the self-regeneration of chirality centers concept discussed in Chapter 3 (c/., Scheme 3.9 and 3.10). After the addition, hydrolytic removal of the achiral auxiliary (pivaldehyde) liberates a 3-alkyl-3-hydroxybutyrate that is essentially enantiomerically pure [134]. 

The reaction of ( S)-1 with isobutyraldehyde in benzene provides a 92 8 mixture of cis-44 and trans-45, whereas the same reaction with pivaldehyde affords only cis-46 in 74% yield. The reaction of ( S)-1 with pivaldehyde dimethyl acetal in the presence of pyridinium p-toluenesulfonate in a refluxing mixture of cyclohexane-ethyl acetate provides a 97 3 cis trans mixture of 46, but in only 25% yield [10]. Treatment of 46 with LDA at —70 °C followed by alkylation with methyl iodide proceeds in 94% yield to provide a 93 7 mixture of cis, trans isomers. Potassium hydroxide hydrolysis affords (5)-( + )-atrolactic acid (47) possessing 85% ee (Scheme 9). 

A milder preparation of these 1,3-dioxolanones is illustrated in Scheme 10, this time utilizing 2. Rhodium triflate, [Rh(CH3CN)3(triphos)] (CF3S03 )3, catalyzed acetalization of pivaldehyde with 2 followed by a single crystallization from ether/pentane furnishes pure cis 50 in high yield (80—90%). Diastereoselective alkylation of the lithium enolate of 50 with... 

Stereoselective aU lation. As an extension of a method for diastereoselective alkylation of a-amino acids (14, 263—264), Seebach et aL have converted this simple -amino acid into the 2-(-butylperhydropyrimidinone 2 via an imine with pivaldehyde. 

The reaction of silylallenes with aldehydes to form dihydrofurans is applicable to a variety of alkyl aldehydes, including substrates such as acetaldehyde (74), cyclohexylaldehyde (77), and pivaldehyde (80). When... 

Krouse and Schrock also made block copolymers with norbornene and PA, using CF3-TCDT (vide supra) as the precursor monomer to polyacetylene (Scheme XVII) [88]. Using ( BuO)2M(N(2,6- Pr)2Ph)(CHR) (M = W, Mo and R = alkyl) to ROMP both monomers allowed for the control of the molecular weight and PDI. Controlling the order of monomer addition allowed for the synthesis of di- and triblock copolymers. The polymerization reaction could be terminated with either benzaldehyde or pivaldehyde to cleave the metal cattil)%t from the propagating polymer chain. Precursor copolymers with norbomene/CF3-TCDT ratios of 1.7 1 to 5 1 could be made with Mn = 6,000-27,000 g/mol and PDI = 1.04-1.23. The elimination of hexaflu-... 

The stereoselective alkylation and aldol reactions of 5-/3-hydroxybutyrolac-tone dianion have been described the highest selectivity was obtained with pivaldehyde and yields are between 40 and 50%. 2,3-O-Isopropylidene-/ -glyceraldehyde (94) is converted into a 3 1 mixture of tribromoacetates (95)/(96) by reaction with carbon tetrabromide and acetylation this mixture is then easily converted into a mixture of diacetyl lactones (Scheme 65). ... 

For the synthesis of 2-pyrrolidone III-16, we followed the procedure described by Germanas and coworkers for the enantioselective alkylation of proline [118]. This procedure was based on a method reported by Seebach [119], in which proline is condensed with pivaldehyde to give a single stereoisomer of 2-f-butyl-l-aza-3-oxabicylo[3.3.0]octan-4-one III-42 [120], which is deprotonated with LDA to give a chiral enolate that can be alkylated with an electrophile (Scheme 4.21). 

The steric bulk of the alkyl group of the aldehyde severely impedes the reaction and for instance, no reaction takes place with pivaldehyde and only 50% is obtained with hydrocinnamaldehyde. Moreover, when a stoichiometric amount of BFj-OEtj was added to N-benzylideneanUine with acylzirconocene chloride, no a-amino ketone was obtained. Lanthanide Lewis acid (3mol% YbjOTfjs/TMSOTf 1 1) is the best solution for the formation of the expected a-amino ketone (Scheme 12.25) [30]. 

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