Tertiary alcohols, formation

The Claisen condensation of t-butyl acetate with a methyl ester is a general route for the preparation of complex P-ketoesters.4 The reaction requires an excess of the enolate of t-butyl acetate to rapidly deprotonate the product and prevent tertiary alcohol formation. Some workers have also used excess LDA or t-butoxide for this purpose. 

Overalkylation can lead to tertiary alcohol formation by consecutive reaction [29]. Product quality demands to keep this impurity level <0.2%. Microreactor operation yielded the overalkylated alcohol follow-up product at 0.18%, whereas level of impurity for the batch process was 1.56% [29]. The reason is probably the lower back-mixing in the microflow system, with concentration profiles being less deteriorated from ideal that is, no excess of alkylating agent is generated locally to promote the follow-up reaction. 

The use of other mixed reagents to promote acylation and subsequent enolization of the ketone during its formation have been reported by Fehr. The success of the method depends on the ease of ketone deprotonation and thus was limited to substituted allylic nucleophiles. The final product was obtained entirely in the form of the a. -unsaturated ketone. A combination of the nucleophilic Grignard reagent and the nonnucleophilic base lithium diisopropylamide converts sterically hinder ester (50) into a-damas-cone (52) via (51) (Scheme 16). The ratio of ketone to tertiary alcohol was 98 2 (many cases gave selectivity greater than 9 1) however, a few examples showed a substantial amount of tertiary alcohol formation. 

AnoAer procedure which was thought to pass through a mixed phosphoms anhydride was the acylation of Grignard reagents with an adduct formed between lithium carboxylates and triphenylphosphine dichloride (Scheme 26). The betaine (70) was the proposed tetrahedral intermediate however, since no evidence is provided, the reaction may have also proceeded by way of the acid chloride. Surprisingly, good yields of ketone are preserved even in the presence of excess nucleophile and no tertiary alcohol formation was observed. Triethylamine can be used for prior deprotonation of the carboxylic acid how-... 

Thomas, A. D., Asokan, C. V. Viismeier-Haack reaction of tertiary alcohols formation of functionalised pyridines and naphthyridines. J. Chem. Soc., Perkin Trans. 1 2001, 2583-2587. 

Ort/io-lithiated aniline derivatives can add to methyl 3-pyridazinecarboxylate to give ketones, though the yields are at best only moderate and reactions of the 4-analogue were still less successful <90JHC1645>. Similarly, addition of dilithiopyrazole to ethyl pyridazinecarboxylates gives 4-pyr-azolyl-3- and 4-pyridazinyl ketones (Equation (18)) tertiary alcohol formation is suppressed by inverse addition <91JHC1189>. 

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