Acylation by acetic anhydride

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

The acylation of aromatic ethers by acyl chlorides is highly regioselective in the presence of 10 mol% Sml3.53 Some aromatic compounds are efficiently acylated by acid anhydrides catalysed by niobium pentachloride with silver perchlorate.54 Arenes of a range of reactivity are acylated by acetic anhydride in a fluorous biphasic system catalysed by Hfps SCLCgFn L (1 mol%)55 The catalyst is easily recoverable and can usually be used again without decrease in activity. 

Other examples are recorded by Hauser and Adams.774 Other acylations by acetic anhydride recorded on previous pages are those of aromatic compounds on page 939, of acetylides on page 931, of alkylcadmiums on page 911, and of diazo compounds on page 948. 

A-Methylimidazole has been used as an effective catalyst of acylation by acetic anhydride. It has a catalytic activity about 4x10 greater than p3uidine (eq 4). ... 

Ethynodiol diacetate (53) is prepared by reduction of the 3-oxo group of norethindrone (28) with lithium tributoxyalurninum hydride, followed by acylation with acetic anhydride-pyridine (78,79). It has been reported that higher yields can be obtained in the reduction step by using triethylanainoalurninum hydride (80). 

The synthesis of 2,4-dihydroxyacetophenone [89-84-9] (21) by acylation reactions of resorcinol has been extensively studied. The reaction is performed using acetic anhydride (104), acetyl chloride (105), or acetic acid (106). The esterification of resorcinol by acetic anhydride followed by the isomerization of the diacetate intermediate has also been described in the presence of zinc chloride (107). Alkylation of resorcinol can be carried out using ethers (108), olefins (109), or alcohols (110). The catalysts which are generally used include sulfuric acid, phosphoric and polyphosphoric acids, acidic resins, or aluminum and iron derivatives. 2-Chlororesorcinol [6201-65-1] (22) is obtained by a sulfonation—chloration—desulfonation technique (111). 1,2,4-Trihydroxybenzene [533-73-3] (23) is obtained by hydroxylation of resorcinol using hydrogen peroxide (112) or peracids (113). 

V-Acylation of oxaziridine (54) is of more importance, yielding 2-acyloxaziridines which were unaccessible otherwise until recently. Oxaziridines (54) derived from cyclohexanone, butanone or benzaldehyde are acylated readily by acetic anhydride, acid chlorides or isocyanates. Oxaziridines from aliphatic aldehydes, too unstable to be isolated, may be trapped in situ by benzoylation (67CB2593). 

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

Idoxuridine Idoxuridine, 5-iodo-1 -(2-deoxyyribofuranosyl)pyrimidin-2,4-(l//.3//)-dione (36.1.14), is synthesized by the following scheme. 5-lodouracil is acylated with acetic anhydride to make l-acetyl-5-iodouracil (36.1.11). Treating this with mercury(ll) acetate gives... 

The association between acetylcholine levels and Alzheimer s disease, as noted more than once previously, has led to the search for novel compounds that raise the level of that neurotransmitter by inhibiting acetylcholinesterase, the agent of its inactivation. The benzisoxazole icopezil (60-8) has undergone several trials against that debilitating disease as a result of selective chohnesterase inhibiting activity in the CNS. Friedel-Crafts acylation of the indolone (60-1) with acetyl chloride affords the methyl ketone (60-2). This is then converted to its oxime and that function acylated with acetic anhydride to yield (60-3). Treatment with pyridinium perbromide... 

Pyrrole and alkylpyrroles are acylated by acid anhydrides above 100°C. Pyrrole itself gives a mixture of 2-acetyl- and 2,5-diacety 1-pyrrole on heating with acetic anhydride at 150-200°C. N-Acylpyrroles are obtained by reaction of the alkali metal salts of pyrrole with an acyl halide. iV-Acetylimidazole efficiently acetylates pyrrole on nitrogen (65CI(L)1426). Pyrrole-2-carbaldehyde is acetylated on nitrogen in 80% yield by reaction with acetic anhydride in methylene chloride and in the presence of triethylamine and 4-dimethylaminopyridine (80CB2036). 

The acetylation of carbazole by acetic anhydride in the presence of boron trifluoride produces the 9-acetyl derivative. Further acetylation requires more vigorous conditions, using aluminum trichloride as a catalyst, and yields 2,9-diacetylcarbazole, which, upon base-catalyzed hydrolysis, produces 2-acetylcarbazole (80T3017). Acetylation of 1-phenyl-isoindole under mild conditions in the presence of pyridine yields l-acetyl-3-phenylisoin-dole, whereas the presence of an ester group at the 1-position deactivates the ring sufficiently to prevent acylation (81AHC(29)34l). 

The simple furan-3(2/f)-ones exist in the keto form but may be O-acylated with acetic anhydride and sodium acetate however, they undergo C-alkylation. They are usually stable to acid, merely being protonated. 4-Alkoxyfuran-3(2//)-ones are readily hydrolyzed to tetronic acids. Furan-3(2//)-ones are degraded by aqueous base which attacks in a conjugate fashion so that 2,5-dimethylfuran-3(2iT)-one, readily available from biacetyl, furnishes acetate and acetoin, but compounds with an ester group at the 4-position furnish tetronic acids (Scheme 109). 

In the case of amino-/3-lactarns, an additional reaction step with acetic anhydride was necessary to protect the amino groups of AMO and AMP (82). This step was also incorporated into the assay for determination of five penicillins (AMO, AMP, PenG, PenV, CLO) (83). The previously described methods were modified by replacing the acylating agent, acetic anhydride, with benzoic anhydride this permitted the elution of all derivatives under isocratic conditions within a very short period of time. This modification reduced analysis time per sample from over 1 hour to about 22 min without loss in detection sensitivity (84). 

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