2-Amino-5-alkyl-1,3,4-oxadiazole alkylation

Oxadiazoles, amino-alkylation, 6, 431 as photographic sensitizer, 6, 446 ring cleavage, 6, 434 tautomerism, 6, 381... 

Oxadiazoles are difficult to alkylate, unless the ring contains a strong electron donor group such as an amino substituent. 

Alkyl- and 5-aryl-2-amino-1,3,4-oxadiazoles were prepared by tosyl chloride/pyridine-mediated cyclization of thiosemicarbazides in good yields (79-99%). Interestingly, thiosemicarbazides exhibited a higher rate of cyclization than the corresponding semicarbazides. For example, 171 (X-S) was converted to oxadiazole 172 within 5 h <06JOC9548>. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Alkyl(or aryl)amino-5-aryl-l,3,4-oxadiazoles were earlier successfully obtained on solid support as shown in Scheme 32 <2001TL2583>. 

In vivo, some other heterocyclic systems behave as NO-donors. Typical examples are the 3-amino-4-alkyl or arylalkyl derivatives of l,2,4-oxadiazol-5(4H)one 133 [169, 170]. These products can be synthesised following Scheme 6.25. 

Alkylation of 2-amino-5-(alkyl, aryl, hetaryl)-l,3,4-oxadiazoles is said to occur at the ring N atom (N-3) (94HOU526), but this report remains doubtful. In addition, as others have pointed out, the very low basicity of imidazo[2,l-b][l,3,4]oxadiazoles precludes the isolation of hydrohalides of type 20. 2,6-Diaryl-imidazo[2,l-ft][l,3,4]oxadiazoles 22 can be obtained directly by treatment of 2-amino-5-aryl-l,3,4-oxadiazoles 21 with phenacyl-bromides in ethanol [reflux in a water bath at 70°C ( ) for 5 h] (84MI1). 

Imidates such as (115) react with cyanamide to give A -cyanoamidines (116), while the hydrochloride (117) is transformed to (118). Both (116) and (118) give 3-amino-1,2,4-oxadiazoles on treatment with hydroxylamine (Scheme 50) <81JHC37, 86JMC1540,92JMC369l>. However, other alkyl-idene cyanamides form either mixtures of 3- and 5-amino-1,2,4-oxadiazoles <87JHC275> or exclusively the 5-amino compounds (Equations (25), (26)) <94BCJ307>. 

Alkyl-3-aminoisoxazoles, 5-alkyl-3-amino-l,2,4-oxadiazoles, and 5-alky 1-3-amino-1,2,5-oxa-diazoles, when heated with phenyl isothiocyanate produce the corresponding thioureas (308) (Equation (46)), (310) (Equation (47)) and (312) (Equation (48)) which subsequently rearrange by a common mechanism to yield 1,2,4-thiadiazoles (309), (311), and (313), respectively <84CHEC-I(6)463>. 

In alkaline solution, 0-alkyl hydroxy oxadiazoles are transformed into hydroxy derivatives while the action of amines yields amino-oxa-diazoles. 

Alkyl-2-ainino- bzw. 2-Amino-5-aryl-l,3,4-oxadiazole allgemeine Arbeitsvorschrift234 41S Man lost das Kohlensaure-(2-acyl-hydrazid)-amid in siedendem Phosphoroxichlorid und erhitzt 1 -3 h unter RiickfluB. Die abgekiihlte Losung wird langsam zu Eiswasser gegeben. 

Buscemi, S., Vivona, N. and Caronna, T. (1995) A generalized and efficient synthesis of 3-amino-, 3-(N-alkylamino)-, 3-(N, N-dialkylamino)-5-alkyl-l, 2,4-oxadiazoles by irradiation of 3-alkanoylamino-4-phenyl-l, 2,5-oxadiazoles (furazans). Synthesis, (8), 917-919. 

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