Acylation of Hindered Alcohols

High-yield aq lations of hindered alcohols are of considerable current interest [ 142 ]. Older methods for such reactions involve acetic anhydride, acetyl chloride, and the use of -butyUithium in the presence of an acid chloride. More contemporary approaches include catalysts such as DMAP [143], BujP [144], and 4-pyrrohdinopyridine (PPY),with DMAP being the most popular. Although both BujP and DMAP provide good yields of acylated alcohols, these catalysts have disadvantages. For example, BU3P has a low flash point and DMAP is fairly toxic. 

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Carboxylic acids react with trifluoroacetic anhydride to give mixed anhydrides that are especially useful for the acylation of hindered alcohols and phenols ... 

Acylation. This cage heterocycle (1) is an excellent catalyst for the acylation of hindered alcohols. Acetylation is accelerated in polar solvents (MeCN), but benzoylation is faster in solvents such as benzene. 

The basic nucleophilic poly(iV-alkylacrylamide)-immobilized catalyst 95 was prepared from the active estercopolymer 94 according to the chemistry shown in Eq. 37 [131]. This polymercontained a ca. 8 mol% loading of an analog of ATjAT-dimethylaminopyridine, anucleophilic catalyst that others had immobilized on insoluble cross-linked resins previously. This soluble version was shown to be effective as a catalyst for acylation of hindered alcohols and phenols (Eqs. 38 and 39). This catalyst contained an azo dye as a marker, which facilitated analysis of the phase separation of the polymer-immobilized catalyst. 

Mayr [35] has shown very recently that, for very reactive systems, reaction will proceed without a catalyst. Bromination of phenol is claimed to occur with high / -selectivity [31], but this is unexceptional. A solution of sulphur trioxide in sulphur dioxide is claimed to be an especially mild sul-phonating agent. Sulphonation of toluene gives mainly /7-isomer, with no sulphones. Acylation of hindered alcohols with acid chlorides occurs unusually rapidly at ambient temperature [33] (equation 12.17). 

Electrolytic reduction, apparatus, 52, 23 Enol acetates, acylation of, 52,1 Enol esters, preparation, 52, 39 Epichlorohydrin, with boron trifluoride diethyl therate and dimethyl ether to give trimethyloxonium tetra-fluoroborate, 51,142 ESTERIFICATION OF HINDERED ALCOHOLS f-BUTYL p-TOLUATE,... 

If the alcoholate or the alkylating reagent contains a carboxylic acid ester, acylation of the alcoholate can compete with alkylation. This potential side reaction does not cause trouble in the examples sketched in Scheme 6.14 (first and third reactions), because these esters are sterically hindered and devoid of a hydrogen (no ketene formation can occur) but, as illustrated in Scheme 6.15, less hindered esters can readily undergo transesterification with alcoholates. 

Acyl iodides.1 This reagent converts acyl chlorides into acyl iodides at 25°. In combination with iodine (1 1) it also converts carboxylic acids, esters, and anhydrides into acyl iodides in generally high yield. This reaction in combination with an alcohol is a useful method for transesterification of hindered alcohols. 

In a interesting example of organocatalysis, Suzuki et al. studied the enantioselective acylation of secondary alcohols using chiral NHCs [11,12]. The approach was partly based on the work of Nolan and Hedrick who had independently reported NHC-catalyzed transesterifications [13,14]. The enantioselective acylation was subsequently improved by using more sterically hindered acylating agents such as diphenylacetate derivatives (Scheme 4), leading to selectivity factors (s = kn, ) of up to 80 [15,16]. 

Some 1,2-dihydroisoquinoline-l-ylphosphonates, e.g. (18), have been prepared from trialkyl phosphites, isoquinoline, and a sulfonyl chloride. Quinoline gave similarly the corresponding l,2-dihydroquinoline-2-ylphosphonates. The superbase (19) has been shown to be a very effective catalyst for the acylation of hindered and/or acid-sensitive alcohols with benzoic anhydride a P-acylated intermediate (20) was inferred from NMR data. 

Acylation of Alcohols. Several 4-aminopyridines speed up esterification of hindered alcohols with acid anhydrides by as much as 10 000 fold of these, DMAP is the most commonly used but 4-pyrrolidinopyridine (PPY) and 4-tetramethylguanidinop3ridine are somewhat more effective. DMAP is usually employed in 0.05-0.2 mol equiv amounts. 

AcCl, NaOH, dioxane, Bu4N HSO, 25°, 30 min, 90% yield. Phase-transfer catalysis with tetra-n-butylammionium hydrogen sulfate effects acylation of sterically hindered phenols and selective acylation of a phenol in the presence of an aliphatic secondary alcohol. 

Halogenation of the 7 position also proves compatible with good antiinflammatory activity. Construction of this compound, aclomethasone dipropionate (80), starts by introduction of the required unsaturation at the 6,7 position by dehydrogenation with DDQ (76). The highly hindered nature of the hydroxyl at position 17 requires that a roundabout scheme be used for formation of the corresponding ester. Thus treatment of 76 with ethyl orthoformate affords first the cyclic orthoformate This then rearranges to the 17 ester on exposure to acetic acid. Acylation of the 21 alcohol is accomplished in straightforward fashion with... 

In a similar vein, acylation of the corticoid 50 with furoyl chloride gives the diacyl derivative 51. Reduction with sodium borohydride serves to convert the 11-ketone to the alcohol 52. Hydrolysis under mild acid conditions preferentially removes the acyl group at the less hindered 21 position. The hydroxyl group in that derivative (53) is then converted to the mesylate 54. Replacement by chlorine affords mometasone (55) [12]. 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

The inclusion of DMAP to the extent of 5-20 mol % in acylations by acid anhydrides and acyl chlorides increases acylation rates by up to four orders of magnitude and permits successful acylation of tertiary and other hindered alcohols. The reagent combination of an acid anhydride with MgBr2 and a hindered tertiary amine, e.g., ( -Pr)2NC2H5 or 1,2,2,6,6,-pentamethylpiperidine, gives an even more reactive acylation system, which is useful for hindered and sensitive alcohols.105... 

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

Exactly the same considerations apply to the esterification of hindered acids (182) in the reverse direction. It will be noticed that this mechanism requires protonation on the less favoured (cf. p. 240) hydroxyl oxygen atom (185) to allow the formation of the acyl carbocationic intermediate (184). Apart from a number of R3C types, a very well known example is 2,4,6-trimethylbenzoic (mesitoic) acid (186), which will not esterify under ordinary acid-catalysis conditions—and nor will its esters (187) hydrolyse. Dissolving acid or ester in cone. H2S04 and pouring this solution into told alcohol or water, respectively, is. found to effect essentially quantitative esterification or hydrolysis as required the reaction proceeds via the acyl cation (188) ... 

The inclusion of DMAP to the extent of 5-20 mol% in acylations by acid anhydrides and acyl chlorides increases acylation rates by up to four orders of magnitude and permits successful acylation of tertiary and other hindered alcohols. 

More stable iV-acylpyridinium salts can be formed by using 4-(Ar,Ar-dialkyl-amino)pyridines. The salts are less readily hydrolyzed and are effective in the acylation of sterically hindered alcohols (72S619) and in the formation of iV-f-butoxycarbonyl derivatives of a-amino acids in aqueous alkali, for use in peptide synthesis (71CC267). 

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