Rearrangement with Acetic Anhydride

The first studies of the reactions of methylpyrazine A(-oxides with acetic anhydride were carried out by Koelsch and Gumprecht (625). They found that 

5- dimethylpyrazine monoxide reacted with acetic anhydride to form 2-acetoxy-methyl-5-methylpyrazine 2,5-dimethylpyrazine dioxide gave 2-acetoxymethyl-5-methylpyrazine and 2,5-bisacetoxymethylpyrazine and 2-acetoxymethyI-5-methylpyrazine dioxide was partly deoxygenated by acetic anhydride to give 

5- bisacetoxymethylpyrazine, its monoxide, and 2-acetoxymethyl-5-methyl-pyrazine monoxide (625). These workers also based their assignment of the structures of the two isomeric monoxides of 2-methylpyrazine (prepared by oxidation with hydrogen peroxide in acetic acid) on reactions with acetic anhydride. 2-Methylpyrazine 1-oxide gave an acetate saponified to 2-hydroxymethylpyrazine (625) and 3-methylpyrazine 1-oxide was claimed to give an acetate saponified to 2-hydroxy-5-methylpyrazine (625), but this has been disputed (760) Asao (738) and Klein et al. (760) claim that 3-methylpyrazine 1-oxide (2-methylpyrazine 4-oxide) does not react with acetic anhydride. 

Details of these and other studies are summarized in Table IV.2 (113b, 625, 737-739,758,760,760a). 

Klein et al. (760) observed that acetoxymethylpyrazines were formed only when a methyl group was adjacent to the A(-oxide function, and they proposed, for these reactions, the mechanism shown in the transformation (36 - 39). 

---

Balfourodine was reported to rearrange with acetic anhydride and pyridine into (+)-isobalfourodine acetate (122), which was hydrolyzed to (-t-)-isobalfourodine (overall 48% racemization), but it is now known that these products are derived from (+)-balfourodine rather than from the levorotatory enantiomer. Because (+)-balfourodine occurs in Balfourodendron riedelianum, and there is no indication that (—)-balfourodine was available from another source, it appears probable that (—)-balfourodine is a misprint for (+)-balfourodine in the earlier paper. Alternative mechanisms involving inversion at the chiral center were proposed for the rearrangement of balfourodine effected by acetic anhydride... 

The Curtius rearrangement in acetic anhydride of the azide (8) prepared from 4-carboxythiazole yields 4-acetamidothiazole (Scheme 8) (47). The same reaction starting with ethyl-2-methyl-4-thiazolyl carboxy-late, failed to give the 4-aminothiazole (48). Heterocyclizations are more convenient synthetic methods (Chapter II. Table 40). 

The Curtms rearrangement has been used to prepare 5-aminothiazole (11) (60.61), 4-methyl-5-aminothiazole. 2-chloro-5-aminothiazole (58), and 2.4-dimethyl-5-aminothiazole (62) (Scheme 11). Heating the corresponding azides yield carbamates that resist hydrolysis but react with acetic anhydride to give the 5-acetylaminothiazoles. 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

A useful approach to the substitution of ring C—H positions lies in the activation of the heteroaromatic system by an A-oxide group, initiating a formal intramolecular redox reaction. 1-Methyllumazine 5-oxide reacts with acetic anhydride in a Katada rearrangement... 

Vapour phase pyrolysis of sulfoximides (529) results in the formation of the nitriles (530) (75JCS(Pl)4l). The tosylate (273), when treated with acetic anhydride, rearranges to (531)... 

Ring enlargement of A-acyl compounds, generally observed with oxaziridines, is observed only occasionally with diaziridines. Under more forced conditions of acylation with acetic anhydride, oxadiazolines like (139) were obtained (76MIP50800). A 4-nitrobenzoyl derivative rearranged at room temperature (76JOC3229). 

Katada, working in the labs of Ochiai, first described the reaction of N-oxide 3 with acetic anhydride. The resultant rearrangement produced a-pyridone 4. Shortly... 

Benzodiazepinones also undergo rearrangement to isoindoles when treated with acetic anhydride and pyridine (Py). The diazepinone (81), for instance, gives l-phenyl-3-acetylisoindole (82) under these conditions. The structure of the product was established in this case by comparison with (82) prepared by acetylation of 1-phenyl-isoindole. The rearrangement may be formally represented by a... 

It has been reported that 6-aminouraeil and di-(2,4-diehlorophenyl)-benzylmalonate yield the pyrimido[l,2-c]pyrimidine (76),although no proof of structure was offered. Treatment of the j8-(pyrimidin-6-ylamino)propionie acid (77) with acetic anhydride, however, has been shown to yield compound 78 by rearrangement. ... 

Lormetazepam (84) is readily synthesized by Polonovski rearrangement of benzodiazepine oxide derivative by heating with acetic anhydride followed by saponification of the resulting rearranged ester.The mechanism of this rearrangement to... 

According to REM, hydrazine hydrate Is reacted with 2 mols of ammonium thiocyanate to produce 1,2-bislthlocarbamoyl) hydrazine which by loss of ammonia and rearrangement produces 5-amino-2-mercapto-1,3,4-thiadiazole. That compound is acetyied with acetic anhydride. 

The Pummerer reaction346 of conformationally rigid 4-aryl-substituted thiane oxides with acetic anhydride was either stereoselective or stereospecific, and the rearrangement is mainly intermolecular, while the rate-determining step appears to be the E2 1,2-elimination of acetic acid from the acetoxysulfonium intermediates formed in the initial acetylation of the sulfoxide. The thermodynamically controlled product is the axial acetoxy isomer, while the kinetically controlled product is the equatorial isomer that is preferentially formed due to the facile access of the acetate to the equatorial position347. The overall mechanism is illustrated in equation 129. 

In 1979, workers investigating " the dienone-phenol rearrangement treated (3) with acetic anhydride and got an unknown compound believed to be (4), Treatment with strong acid gave (5), they supposed, but they wanted to synthesise an authentic sample of (5) to check their assignment. This is a tricky problem... 

In acetic acid, or aqueous acetone with subsequent treatment with acetic anhydride, the esters (196 R=4-Me0 or 4-MeS) give rise to the expected esters(197) or (198). For the 4-chlorophenyl derivative, a mixture of the unexpected products (199, 200 Ar=4-chlorophenyl) was obtained. The unsubstituted compound (196 R=H) gave only (199) in aqueous acetone, but (200) in acetic acid. The postulated mechanism tor such a rearrangement centres around pseudophosphonium and-or phosphorane... 

It will perhaps be recalled from the earlier volume that such N-oxides are prone to undergo the Polonovski rearrangement when treated with acetic anhydride, and that this was illustrated by the formation of oxazepam. It is not surprising that the N-methyl analogue (4) also undergoes this process, and hydrolysis of the resulting acetate gives... 

Monosulfoxide 13 undergoes the Pummerer rearrangement when treated with acetic anhydride in the presence of sodium acetate.85 The experiments with tetradeuterated and 180-labeled sulfoxide confirm intermediate formation of a dication.86 The ratio of 2,8,8-trideuteriated to 4,4,6,6-tetradeuteriated product 37 is equal to the intramolecular isotope effect ku k0 =1.7 (Scheme 21).85... 

Interesting Dimroth rearrangements in cytosine and its derivatives occur when they are allowed to react with acetic anhydride-acetic acid. Cyto-... 

---