Acetic anhydride heterocycle acylation

The aromaticity of the imidazole nucleus ensures stability towards reduction, and when benzimidazole (27) is hydrogenated over Adams catalyst in acetic acid the carbocyclic ring is reduced first to give the tetrahydrobenzimidazole (28). However, if the solvent is changed to acetic anhydride, A(-acylation promotes the reduction of the heterocycle and the 1,3-diacetylbenzimidazoline (29) is then formed (Scheme 1). Imidazole (30) under these conditions gives 1,3-diacetylimidazoline (31). Imidazolium salts (32) are easily reduced and treatment with excess sodium borohydride in 95% aqueous ethanol culminates in the formation of 1,2-diamines, (33) or (34). Either N—C bond may cleave, although if the substituent R is benzyl the major products are benzylamines (33 R = Bn). ... 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Azido derivatives of furazans have proved to be particularly useful for the synthesis of heterocyclic systems. Thus, by 1,3-dipolar addition of l-azido(4-amino-l,2,5-oxadiazol-3-yl)aldoxime 186 to propargyl alcohol and phenylacetyl-ene, bicyclic 4-amino-l,2,5-oxadiazol-3-yl(4-R-l,2,3-triazol-l-yl)ketoximes 187 were obtained (Equation 34) which in reaction with acetic anhydride afforded the corresponding 0-acyl derivatives <2003RJ0574>. 

Among the NO-donor mesoinoic heterocycles, the sydnonimines have attracted by far the most interest. They were first obtained by Brookes et al. [78] and Kato et al. [79] by the action of nitrous fumes on a-( N-rnelh yl-N-riilrosoamino)-nitriles followed by the action of acetic anhydride. Whereas sydnones represent a family of stable heterocycles, sydnonimines, with the exception of 3-hydroxysydnonimine (81, R=OH, Ri =H) that forms an inner salt [80], are unstable if not protonated to a salt or acylated to stable N-acylimino derivatives. In this case they can be stored at room temperature... 

Examples of the reaction of pyrroles and indoles in acidic media with 77-electron-excessive heterocycles are discussed in Section 3.05.1.2.2 and elsewhere. However, for comparison of the reaction conditions, it is of interest to note, for example, the reaction of indole with an acyl chloride in the presence of a 7r-electron-excessive heterocycle, such as thiophene or furan, to yield the 3-acyl-2-heteroarylindoline (78KGS561, 79KGS493), the reaction of pyrroles and indoles with imidazole and benzimidazole in the presence of acetic anhydride to yield the iV,iV -diacetylimidazoline derivatives of the indoles and pyrroles (80T2505), and the formation of 2-heteroaryl-3,3-dimethylindolines from the reaction of 3,3-dimethyl-3Ef-indoles with indoles or pyrroles (77S343). 

Some acyl halides are reactive enough to effect Friedel-Crafts acylation on the neutral heterocycles without a catalyst. For pyrrole such reactions are known, for example, with trifluoroacetyl chloride and trichloroacetyl chloride. Indole reacts smoothly in cold ether with oxalyl chloride and on heating with acetic anhydride. Some examples of these types of acylation are collected in Table 10. 

POLONOVSKI REACTION. Demethylation of tertiary (or Heterocyclic) amine A-oxides on treatment with acetyl chloride or acetic anhydride 1o give A-acylated secondary amines and formaldehyde, along with (9-acylated aminophenols as a result of a side reaction. 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

Acylation of heterocyclics, such as thiophene, seems to require a lower acid strength of the catalyst which is best met by B-ZSM-5. The reaction of thiophene with acetic anhydride to 2-acetylthiophene proceeds with 99% selectivity at 24% conversion and the conversion of pyrrole with acetic anhydride to 2-acetylpyrrole with 98% selectivity at 41% conversion [115]. 

The use of acetic anhydride as the solvent facilitates432 intermolecu-lar iodide displacements at C-5 of 156. Acylation of the heterocyclic base occurred at N-l (as indicated by infrared spectroscopy) during the reaction, and this inhibited occurrence of intramolecular displacement. The electron-withdrawing effect of the acyl group presumably diminishes the nucleophilicity at N-3. N-Formyl-2, 3 -0-iso-propylidene-5 -0-p-tolylsulfonyladenosine also reacts intermolecu-larly with lithium chloride or sodium azide in methyl sulfoxide to give 5 -chloro and 5 -azido derivatives.432... 

Acetic anhydride and aluminum chloride in caibon disulfide gives a high yield of the para-acylated product with thioanisole, and in dichloromethane the same reagents give an almost quantitative yield of 3-acetyl-1-benzenesulfonylindole. Acylation of more nucleophilic heterocycles can be achieved using milder catalysts, such as zinc chloride. It has been known for some time that furan can be acylated very efficiently using acetic anhydride and zinc chloride. The Paal-Knorr furan synthesis (1,4-diketone, acetic anhydride and zinc chloride) can sometimes result in acylation as well as cyclization (equation 40). - Equations (41) and (42) further exemplify the acylation of furan derivatives that have been used in the synthesis of cytotoxic furanonaphthoquinones. 

Acylation of heterocyclics on R-exchanged zeolites has been also reported. This is the case for the acylation of furan with acetic anhydride to form 2-acetylfuran Ce,B- and La,B-ZSM-5 catalysts (Lermer et al. 1987) or the acylation of substituted benzofuran (Amouzegh et al. 1995). 

In aromatic acylation, present industrial practice involves stoichiometric amounts of metal halides as "catalysts" and of acylating agents. Aromatic heterocycles present exceptions. For example, catalytic amounts of SnCU promote the reaction of benzofuran with acetic anhydride to give 4()% 2-acetyl-benzofuran [1]. 

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