Tertiary alcohols acylation

In general reaction of an alcohol with the appropriate anhydride or acid chloride in pyridine at 0-20 JC is sufficient. In the case of tertiary alcohols, acylation is very slow in which case a catalytic amount of 4-dimethylaminopyridine (DMAP) can be added to speed up the reaction by a factor of 10,000. Reaction of polyols with acyl chlorides (1.2 equiv) in the presence of hindered bases (2.0equiv) such as 2,4,6-collidine, diisopropylethylamine or 1,2,2,6,6-penta-methylpiperidine in dichloromethane at -78 °C leads to selective acylation of a primary alcohol. Primary alcohols can also be acylated selectively with isopro-penyl acetate or acetic anhydride in the presence of a catalytic amount of 1,3-dichlorotetrabutyldistannoxane 325.1 [Scheme 4.325].602 The catalyst 325.1 is available commercially or can be easily prepared by simply mixing dibutyltin oxide and dibutyldichlorostannane. No aqueous workup is necessary since the catalyst can be removed by simple chromatography. 

Chiral diene—iron tricarbonyl complexes were acylated using aluminum chloride to give acylated diene—iron complexes with high enantiomeric purity (>96% ee). For example, /ra/ j -piperjdene—iron tricarbonyl reacted with acyl haUdes under Friedel-Crafts conditions to give l-acyl-l,3-pentadiene—iron tricarbonyl complex without any racemization. These complexes can be converted to a variety of enantiomericaHy pure tertiary alcohols (180). 

Acyl (or 4-hydroxymethylene) isoxazolin-5-ones react with Grignard reagents to give 4-methyleneisoxazolin-5-ones (Scheme 57) 72M141613, 73UC1). In contrast, 4-acylisoxazol-ium salts under the same conditions produced tertiary alcohols (Scheme 57) (75MI41617). 

AC2O, Pyr, 20°, 12 h, 100% yield. This is one of the most common methods for acetate introduction. By running the reaction at lower temperatures good selectivity pan be achieved for primary alcohols over secondary alcohols. Tertiary alcohols are generally not acylated under these conditions. 

AC2O, AcCl, Pyr, DMAP, 24-80°, 1-40 h, 72-95% yield. The use of DMAP increases the rate of acylation by a factor of 10. These conditions will acylate most alcohols, including tertiary alcohols. The use of DMAP (4-N,N-dimethylaminopyridine) as a catalyst to improve the rate of esterification is quite general and works for other esters as well. 

BZ2O, MgBr2, TEA, CH2CI2, it, 95% yield. Tertiary alcohols are readily acylated. ... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Tertiary alkyl azides can be prepared by stirring tertiary alkyl chlorides with NaN3 and ZnCl2 in 82 ° or by treating tertiary alcohols with NaN3 and CF3-COOH or with HN3 andTiCl4 or BF3. Acyl azides, which can be used in the Curtius reaction (18-14), can be similarly prepared from acyl halides, anhydrides, " esters, or other acyl derivatives. ° Acyl azides can also be prepared... 

The acylation of tertiary alcohols can be effected by use of Sc(03SCF3)3 with diisopropylcarbodiimide (D-/-PCI) and DMAP.109... 

This method was effective for acylation of a hindered tertiary alcohol in the anticancer agent camptothecin by protected amino acids. 

Trimethylsilyl triflate is also a powerful catalyst for acylation by anhydrides. Reactions of alcohols with a modest excess (1.5 equival) of anhydride proceed in inert solvents at 0°C. Even tertiary alcohols react rapidly.114 The active acylation reagent is presumably generated by O-silylation of the anhydride. 

Ketones can also be prepared from acyl chlorides by reaction at low temperature using an excess of acyl chloride. Tetrahydrofuran is the preferred solvent.91 The reaction conditions must be carefully controlled to prevent formation of tertiary alcohol by addition of a Grignard reagent to the ketone as it is formed. 

The resolution of primary or secondary alcohols is easy by enzymatic acylation however, few examples have been described for the resolution of tertiary alcohols [26]. 

The abundance of fatty acids in triacylglycerols (TAG) can be determined by conversion of the acyl groups into tertiary alcohols on reaction with an alkyl Grignard reagent, followed by chromatographic separation. The method was found to be of advantage over saponification and conversion to a methyl ester, especially in the determination of short-chain fatty acids, which suffer losses by volatilization. ... 

Essentially the same route is followed for the synthesis of the triphenylethylene nitromifene (8-5). The sequence starts with Friedel-Crafts acylation of the alkylation product (8-1) from phenol and 1,2-dibromoethane with the acid chloride from anisic acid (8-2). The displacement of bromine in the product (8-3) with pyrrolidine leads to the formation of the basic ether and thus (8-4). Condensation of that product with benzylmagnesium bromide gives the tertiary alcohol (8-5). This product is then treated with a mixture of nitric and acetic acids. The dehydration products from the first step almost certainly consist of a mixture of the E and Z isomers for the same reasons advanced above. The olefin undergoes nitration under reaction conditions to lead to nitromifene (8-6) as a mixture of isomers [8] the separated compounds are reported to show surprisingly equivalent agonist/antagonist activities. 

Tertiary alcohols are very unreactive toward hydrolases. There are, however, exceptions. Some enzymes have a certain amino acid motif located in the oxyanion binding pocket that allows the docking of space-demanding alcohols such as tertiary ones into the acylated enzyme [104]. One such hydrolase is Candida antarctica lipase A (CALA), which has been found to catalyze the acylation of the tertiary 2-phenyl-3-butyn-2-ol rac-110 by vinyl acetate in organic solvents. Thus efficient resolution of 110 was achieved in isooctane at room temperature (Scheme 4.34) [105]. 

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