Hydroxy Alkylation with Carbonyl Compounds

Competitive experiments have been made in THF at —78 °C with benzaldehyde and 5 molar equivalents of phenylthiocyclopropyllithium and 5 equivalents of one of the two seleno derivatives. Recovery of equal amounts of the p-hydroxysulfide and the P-hydroxyselenide leads to the assumption that these derivatives possess similar nucleophilicities, at least towards this aldehyde. 

As a general trend, a-seleno- and a-silylcyclopropyllithiuras have a very large tendency to add on to the carbonyl group of oc-enals and a-enones. They share this 

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Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

An early effort to generate a 3-lithiated propionic acid derivative and react it with (external) electrophiles was reported in 1978 [42]. Since simple 3-lithioesters failed to undergo the required reaction, the alkyl carboxylate portion was protected by preceding conversion to the carboxylate anion. Treatment of lithium 3-bromo-propionate with lithium naphthalide generated the desired dilithiated propionic acid, which gave moderate yields of y-hydroxy acid addition products with carbonyl compounds, Eq. (45). 

Substituted cyclobutenes 2-substituted 1,3-dienes. The reagent reacts with various electrophiles (alkyl halides, carbonyl compounds, epoxides) to give the corresponding selenides, jS-hydroxy- and y-hydroxyselenides, respectively. Three methods can be used to convert these adducts to cyclobutenes, as shown in equations... 

Similar reactions were performed with dioxolanes 400 bearing abstractable hydrogen atoms in the 2-position (Fig. 93) [436]. Radical addition to acceptors 401 and oxygenation gave protected 2-hydroxy-4-oxo carbonyl compounds 402 in 16-84% yield. For these substrates a catalyst system of 0.1 mol% Co(OAc)2 and 5 mol% 398 proved to be sufficient to achieve good yields. Low yields were only obtained with (i-alkyl-substituted substrates 401. Methyl vinyl ketone undergoes a fragmentation under the reaction conditions. 

Reactions of the Enolate of (1) with Electrophiles. Addition of the dioxolanones (1) to solutions of Lithium Diiso-propylamide or Lithium Hexamethyldisilazide in THF at dry-ice temperature generates the corresponding enolates which react with alkyl halides, - carbonyl compounds, and nitroalkenes almost exclusively from the face remote from the t-Bu group to give products of type (2). These can be hydrolyzed to simple ot-hydroxy-ot-methyl carboxylic acids or further elaborated. Four examples are shown in (3)-(6) in which the part of the molecule originating from lactic acid is indicated in bold. 

The reactions of metailated 2-methyloxazolines with carbonyl compounds to provide adducts constitute the key step in a general procedure for the conversion of carbonyl compounds into 3-hydroxy carboxylic acids and esters or their a,3-unsaturated counterparts (Schemes 21-26). o For example, reaction of the lithiated derivative of (54) with carbonyl compounds provides the adducts (55) in high yield (Scheme 21). Subsequent acid-catalyzed hydrolysis provides the unsaturated carboxylic acids (56) depending upon the severity of the reaction conditions, acid-induced ethanolysis can be performed on the adducts (55) to provide either the unsaturated esters (57) or the 3-hydroxy esters (58) in good yields (Table 7). The main limitation of the method is that extensive retroaldolization occurs upon attempts to hydrolyze adducts (55 R = alkyl), so a-alkyl-3-hydroxy esters and acids do not appear to be accessible. 

Alkylation of carbonyl compounds and derivatives. The 02/Co(OAc)2-Mn(OAc)2 system is useful to accomplish a-alkylation of ketones with 1-alkenes. Acetals also add to acrylic esters under O2 in the presence of catalytic amounts of Co(OAc)2 and A-hydroxyphthalimide to afford a-hydroxy-y-oxo ester acetals. The adducts of methyl vinyl ketone suffer oxidative degradation in situ. 

Such copolymers of oxygen have been prepared from styrene, a-methylstyrene, indene, ketenes, butadiene, isoprene, l,l-diphen5iethylene, methyl methacrjiate, methyl acrylate, acrylonitrile, and vinyl chloride (44,66,109). 1,3-Dienes, such as butadiene, yield randomly distributed 1,2- and 1,4-copolymers. Oxygen pressure and olefin stmcture are important factors in these reactions for example, other products, eg, carbonyl compounds, epoxides, etc, can form at low oxygen pressures. Polymers possessing dialkyl peroxide moieties in the polymer backbone have also been prepared by base-catalyzed condensations of di(hydroxy-/ f2 -alkyl) peroxides with dibasic acid chlorides or bis(chloroformates) (110). 

The procedure involves C-alkylation of an a-sulfonyl carbanion derived from 245 with alkyl halides or carbonyl compounds, followed by cleavage of the cyclopropanols 247 produced by deprotection of the hydroxy group of 246 to give (E)-substituted aldehydes141. 

Table 2.5 Formation of optically active functionalized fS-hydroxy-nitroncs 95 by reaction of aldehydes 93 with activated carbonyl compounds 94 and substituted N -alkyl hydroxylamine hydrochloride in the presence of L-proline as the catalyst...

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