2- Amino-l,3,4-oxadiazoles

Amino-l,3,4-oxadiazoles (423) ring-open and the products immediately recyclize to triazolinones (424) (66AHC(7)183). 

Two variations of the transformation of 3-acyltetrazoles into oxadiazoles are useful from a synthetic point of view. The first transformation involves the reaction of tetrazole with diketene. In the second, the sodium salt of the tetrazole is treated with oxalyl chloride. UV irradiation of some 3-amino-l,2,4-oxadiazoles leads to the formation of the corresponding 2-amino-l,3,4-oxadiazoles <1996CHEC-II(4)268>. 

Treatment of 2-amino-l,3,4-oxadiazoles 13 with bromoketones in boiling ethanol gives imidazo[2,l-h][l,3,4]oxadiazoles 20 directly (isolated as salts (82JIC1170).2... 

Amino-l,3,4-oxadiazole und ihre Dcrivate wirken muskelrelaxicrcnd96, anticonvulsiv97, antiallergisch98 99 analgetisch100, und als MAO- und Cholinesterase-rnhibitoren101. 

Amino-l,3,4-oxadiazole allgemeine Arbeitsvorschrift2 72 Eine Losung oder Suspension von 5 mmol Car-bonsaure-hydrazid in 1,4-Dioxan wird auf 5- 10c abgekiihlt und unter Riihren und ICuhlen mit 0,60 g (5 mmol) Phenylcyanat in 3 ml 1,4-Dioxan versetzt. Nach 10-30 min fallt das 2-Amino-1.3,4-oxadiazol in Ausbeuten von 50-80% aus. 

Anstelle von Phenylcyanat konnen auch Alkylcyanate wie 2,2,2-Trichlor- und 2,2,2-Trifluor-ethylcyanat mit Carbonsaure-hydraziden zu 2-Amino-l,3,4-oxadiazolen cyclisieren2 4. Diese Reaktion erfolgt tiber eine Addition des Alkylcyanats zu Kohlensa ure-(2-acyI-hydrazid)-alkylamiden, die beim Erwarmen 2-Amino-l,3,4-oxadiazole liefern2 4. 

Tab.44 2-Amino-l,3,4-oxadiazole aus Monoacyl-hydrazinen mit Bromcyan Mcthodc Eintopfverfahren nach den allgemeinen Vorschriften (s. S. 549f.)...

Bei der Cyclisierimg von [(Amino-thiocarbonyl)-hydrazono]-essigsaure-butylester mit Iod/Ka-Humiodid und Natriumcarbonat erhalt man 2-Amino-5-curboxy-l, 3,4-oxadiazol(49% Schmp. 128°)487, das leicht zu 2-Amino-l,3,4-oxadiazol decarboxyliert wird (vgl. S. 600) ... 

Amino-l,3,4-oxadiazole konnen fur die Einfuhrung heterocyclischer Substituenten iiber eine Ringumwandlung eines anderen labilen Heterocyclus genutzt werden. So reagiert 2-Amino-5-phenyl-l,3,4-oxadiazol mit 4-Benzyliden-2-methyl-5-oxo-4,5-dihydro-l,3-oxazol zu 2-(4-Benzyliden-2-methyl-5-oxo-4,5-dihydro-lH-imidazolo)-5-phenyl-1,3,4-oxadiazol649 (70% Schmp. 258°). 

Bei der Umsetzung von 2-Amino-l,3,4-oxadiazol mit Aroylisothiocyanaten bzw. einer Mi-schung von Aroylchlorid und Ammoniumthiocyanat gelangt man nicht zu 1,3,4-Oxadiazo-lo[3,2-a]-l,3,5-triazinen671. Uber ein 2-(3-Acyl-2-thioureido)-l,3,4-oxadiazol erhalt man viel-mehr 6-Aroylimino-6H-[Pg.611]

Amino-l,3,4-oxadiazole und Oxalylchlorid reagieren zu 5,6-Dioxo-5,6-dihydro-, die sich thermisch zu 5,7-Dioxo-6-(l,3,4-oxadiazol-2-yl)-6,7-dihydro-5H-[Pg.612]

Amino-l,3,4-oxadiazole reagieren mit (Ethoxy-methylen)-malonsaure-diethylester zu 2-(Di-ethoxycarbonyl-ethenylamino)-l,3,4-oxadiazolen678,686 581, die sich zu 2-substituier-ten 6-Ethoxycarbonyl-5-oxo-5H-[Pg.613]

Mit Acyl-hydrazinen lassen sich ebenfalls 2-Amino-l,3,4-oxadiazole zunachst zu Kohlensau-re-bis-[2-acyl-hydrazid]-imiden261 654 734 spalten, die zu 1,2,4-Triazolen eyclisicrt werden konnen. 

Thio)Kohlensaure-amid-hydrazid-Hydrochloride spalten 2-Amino-l,3,4-oxadiazole zu Koh-lensaure-(2-acyl-hydrazid)-(2-ami nocar bo nyl-hydrazid)-imiden bzw. -(2-acyl-hy-drazid)-[2-(amino-thiocarbonyl)-hydrazid]-imid-Hydrochloriden, die sich z.B. mit 2N Natronlaugc zu 3-(Aminocarbonyl-hydrazino)- bzw. 3-[(Amino-thiocarbonyl)-hydrazino]-l,2,4-triazolen cyclisieren lassen737-784,785 ... 

Amino-l,3,4-oxadiazoles (205) on treatment with cr-halogeno-ketones gave intermediate quaternary salts 206 that did not cyclize directly to imidazo[2,l-6]oxadiazoles (208) with base. Hydrolysis of 206 with aqueous potassium carbonate caused ring-opening at C-2 with subsequent closure to the imidazolone 207. These latter compounds could be cyclized to 208 with phosphorus oxychloride.204c 21 246... 

Hydroxy- (8a), 2-mercapto- (8b) and 2-amino-l,3,4-oxadiazoles (8c) are in equilibrium with the tautomeric oxadiazolines (9a), (9b) and (9c) respectively. Evidence from UV (72CJC3079) and IR (Section 4.23.2.2.3) spectra supports structure (9a) for A2-l,3,4-oxadiazolin-5-ones and structure (9b) for A2-l,3,4-oxadiazoline-5-thiones. The UV and IR spectra, fluorescence and p/iT values of 2-amino-l,3,4-oxadiazoles indicate that the amine tautomer (8c or d) rather than the imine tautomer (9c or d) predominates (69BSF870, 874, 64CR(258)4579>. 

Amino-l,3,4-oxadiazoles form amides with acetic anhydride, benzoyl chloride and arenesulfonyl chlorides. With phenyl isocyanate, 5-substituted 2-amino-l,3,4-oxadiazoles yield urea derivatives (71a). Using an excess of phenyl isocyanate an isocyanate (71b) is produced, and with three equivalents of phenyl isocyanate l,3,4-oxadiazolo[3,2-a]-l,3,5-triazine-5,7-diones are obtained (Chapter 4.29) (74T221). 

Imidophosphoranes (7le) (80JIC1243) or phosphorimidic trichlorides (71f) (79JHC1097) are formed when 2-aminooxadiazoles react with dibromotriphenylphosphorane or phosphorus pentachloride respectively. 2-Amino-l,3,4-oxadiazoles form silver and copper salts and yield complexes with heavy metal salts (62ZC69). 

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. 

Isocyanide dichlorides, formally imines derived from phosgene, react in a manner similar to that of phosgene (above) except that 2-amino-l,3,4-oxadiazole derivatives, instead of oxadiazolin-5-ones, are produced (Scheme 15) (71CC1223,81AP193,73CHE1216). 

Azole approach. Because 2-amino-l,3,4-oxadiazoles are readily available, they are commonly used as starting materials in the preparation of fused pyrimidines. The 2-amines... 

Acid hydrazides and 4-arylsemicarbazides [Eq. (5), R=NHAr] cyclize on heating for a short time with an excess of phenylisocyanide-dichloride to give 2-amino-l,3,4-oxadiazoles [Eq. (5)].92... 

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