Cyclization agents/cyclizations acetic anhydride

The second most popular method of oxadiazole preparation starts from acylhydrazones 110, which undergo cyclization usually under the action of oxidizing agents (Br2, PhN02, HgO, iodobenzene diacetate). Also, the use of acetic anhydride can lead to cyclization of compound 110. The cyclization can be supported by microwave irradiation. In particular cases, heating is sufficient to accomplish the reaction. 

It was shown previously that saturated 5(4//)-oxazolones or 2-oxazolm-5-ones with only one substituent at C-4 can be considered as the tautomeric form of saturated 5(2//)-oxazolones or 3-oxazolin-5-ones. These compounds can also be considered as amino acid derivatives and, indeed, cyclization procedures are the most commonly used to prepare these compounds. The cyclization reaction employs a variety of cyclodehydrating agents and the general method is shown in Scheme 7.23, with an A-acyl-a-amino acid being the most typical starting material used. In this way, 5(4//)-oxazolones derived from most natural amino acids 99 (R3 = H) have been obtained by heating the corresponding A-acyl derivatives in the presence of acetic anhydride. 

Triethyl orthoformate has proved to be a useful cyclizing agent, especially when mixed with acetic anhydride which produces diethoxymethyl acetate (56JA1928,56JOC599, B-78MI40903, p. 995). 

The most general and probably the best method for synthesizing 9-aminopurines makes use of the cyclization of suitable 5-amino-6-hydrazi-nopyrimidines. As cyclizing agents, formic acid or ortho-formates are often used the best mixture is of ort/io-formate and acetic anhydride. The cyclization process is often accompanied by side reactions [Eq. (27)]. 

The reactions shown in this section illustrate the versatility of Af-substituted pyridines in the synthesis of condensed heterocycles containing pyrrole. Some of the cyclizations proceed without the need for externally applied heat [2419, 2422,2830,2980a], and for most of the cyclizations, the conditions are relatively mild. The preformed ylide is used in some of the reactions while in others, it is generated in situ. It is even possible to react a 2-methylpyridine with an Af-alkyl-ating agent, such as bromoacetone, and then cyclize the intermediate iV-alkyl derivative by heating with sodium acetate-acetic anhydride or carbonate without isolating either the intermediate. /V-alkylpyridine or the ylide [2157, 2295, 2393, 3512]. 

The bis-a-haloamides, resulting from the reaction of 1,3-diazaadamantanes with a-halo derivatives of acetic anhydrid or chloracetic acid (95, 96), are useful agents for cyclization reactions (35, 97-99), following known cyclization methods (100), to yield the macrocyclic compounds 71-74 (see Chart 8). Other interesting macrocyclic bispidine compounds with crown ether fragments were also described (101). 

The mechanism of cyclization with ortho esters differs from that of simple acylating agents, such as acetic anhydride, in that the aromatic rather than the aliphatic primary amino group is the first site of attack. The extended conjugation that arises in this way, as in 65 for example, promotes the reaction. Ring closure is aided by the loss of the —OEt group and by its... 

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