Cyclization agents/cyclizations phosphorus oxychloride

Shifting the side chain to the 4 position (with the necessary tautomeric change) affords an agent with local anesthetic and coronary vasodilator activity. Cyclization of compound 147 by means of phosphorus oxychloride gives the amino-l,2,4-oxodiazole (148) Alkylation of that compound with 2-chlorotriethylamine in the presence of sodium hydroxide proceeds via the tautomer,... 

The key intermediate chloromethyloxadiazole 18 was prepared in two steps from inexpensive, commercially available materials as shown in Scheme 5.10. Bishydrazide 19 was prepared in a one-pot procedure by reaction of 35% aqueous hydrazine with ethyl trifluoroacetate in acetonitrile and subsequent addition of chloroacetyl chloride and base. This procedure affords the unsymmetrical bis(hydrazide) 19 in higher than 95% assay yield. While a number of dehydrating agents were found to be effective in the dehydration to prepare 18, phosphorus oxychloride was chosen because of its low cost and relatively benign waste stream. Sub-stoichiometric (0.3 equiv.) amounts were found to be as effective as full equivalents in the reachon when used in conjunction with catalyhc amounts of DMAP as a nucleophilic catalyst. The entire sequence was transformed into a one-pot through process in order to improve efficiency. Following the cyclization, an aqueous work-up was performed and the organic extracts carried directly into the next step. 

Cyclization in phosphorus oxychloride of semicarbazides (79 X = NHR) yields aminooxadiazoles (81) whereas thermolysis leads to loss of ammonia (when X = NH2) and formation of an oxadiazolinone (80). Cyclization to aminooxadiazoles (81) occurs when thiosemicarbazides (82) are heated with an oxidizing agent such as lead oxide. This reaction has been widely applied to the synthesis of aminooxadiazoles, sometimes in low yields, and has been used to prepare 2-amino-l,3,4-oxadiazole (81 R1 =R2 = H). 5-Methyl ethers of thiosemicarbazides (82) cyclize, with loss of methanethiol, to aminooxadiazoles (81) on heating, but in PPA cyclization to 2-methylthio-l,3,4-oxadiazoles occurs. 

Mono- or diacyl derivatives that undergo cyclization to benzoxazoles on heating or under the influence of dehydrating agents are formed as intermediates in this reaction [134, 452, 453, 459, 461 173], Phosphorus oxychloride [453, 457], boric anhydride [455, 461, 462], or polyphosphoric acid [134, 471] are used as condensing agents. In particular, 2-hydroxy-5-nitrobenzoxazole, used for the synthesis of antivirus medicines, has been obtained by the reaction of condensation of 4-nitro-2-aminophenol with (NH2)2CO in pyridine [474],... 

Substituted-2-(2-methyl-4-nitro-1 -imidazomethyl)-1,3,4-oxadiazoles (xxxviii) have been prepared under microwave irradiation using 2-methyl-4-nitro-1-imidazo-acethydrazide (xxxvii), aromatic acid and phosphorus oxychloride as the cyclizing agent [36]. 

As shown in eq. 3 (p. 9) the reaction of acyl arylhydrazines with jS-ketoesters forms 2-aryl-3-pyrazolin-5-ones.679,849,984,988,1001 The aeyl group is lost in the cyclization and these products have no N-l substituent. Formyl-, acetyl- and benzoylhydrazines may be used. This is a very frequently employed method for preparation of 2-aryl-3-pyrazoIin-5-ones. The condensing agents generally used have been phosphorus trichloride, phosphorus oxychloride and phosphorus penta-chloride. A modification of this, also mentioned earlier, has been the condensation of a symmetrically substituted hydrazine with a j8-ketoester to give l,2-disubstituted-3-pyrazolin-5-ones.54,370 The sub-... 

The chemistry of 1,3,4-thiadiazole has been recently reviewed <04MI405>. The 2-substituted 1,3,4-thiadiazoles 258 are formed by the reactions of thiohydrazides 257 with DMF and diethyl chlorophosphate. This cyclodehydrating agent is superior to several commonly used ones such as ethyl orthoformate, ethyl formate or even phosphorus oxychloride for this type of cyclization <04817>. Reaction of/ -tolualdehyde hydrazone 259 with disulfur dichloride in the presence of DBU gives 2,5-di(p-tolyl)-1,3,4-thiadiazole 260 <04S1929>. 

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