1.3.4- Oxadiazoles chlorides

Treatment of intermediate 31 with 2.2 equiv of 4-FB A in EtOH at 72 °C afforded 35 as a white crystalline solid in 90% isolated yield (Scheme 6.9). Hydrogenation in the presence of 5% of Pd/C and 1 equiv of MsOH, efficiently removed the Cbz-protected group. MsOH was used to prevent fluoride reduction resulting in low levels of the des-fluoro by-product. Catalyst filtration, followed by neutralization of the crude reaction mixture with NaOH, afforded free amine 36 as a white crystalline product in 99% isolated yield. Free-amine 36 was isolated as a dihydrate which necessitated drying prior to coupling with oxadiazole chloride 2. 

Reaction of a hydrazide (128) with phosgeneiminium chloride (115) led to the 2-dimethylamino-l,3,4-oxadiazole (129) in 90% yield (75AG(E)806). The 1,3,4-thiadiazole system was also obtained in an analogous reaction in which the dithioimidate (130) underwent reaction with the thiohydrazide (131). Depending on the nature of X in (131), the 2-substituent in the resultant 1,3,4-thiadiazole (132) may be varied (80ZC413). Although (130)... 

Acylation of benzamidoxlme (144) with chloropropionyl chloride gives the 0-acylated derivative (145). Reaction of that intermediate with diethylamine serves first to cyclize the molecule to the 1,2,4-oxadiazole heterocycle subsequent displacement of the halogen on the side chain gives oxolamine (146),a drug with antltussive and spasmolytic activity. 

Oxy-aldehyd, n, hydroxy aldehyde, -ammo-niak, n, oxyammonia (hydroxylamine), -azoverbindung, /. hydroxyazo compound, -benzol, n, hydroxybenzene (phenol), -bem-steinsaure. /, hydroxysuccinic acid (malic acid). -biazol, n. oxadiazole, oxdiazole. -bitumen, n, oxidized bitumen, -carbon-s ure, /, hydroxycarboxylic acid, -chlnoltn, n. hydroxyquinoline, -clunon, n. hydroxy-quinone. -chlorid, n. oxychloride, -chlor-kupfer, n. copper oxychloride, -cyan, n. oxycyanogen. 

The dione 1 is converted into 2,6-dichloro-4,l-benzoxazepin-5(3i/)-one (2) by the action of phosphoryl chloride in jV.lV-dimethylaniline. The crude product on treatment with 3-isocyano-methyl-5-isopropyl-l,2,4-oxadiazole gives the imidazobenzoxazepinone 3.36... 

Benzofurazan (benz-1,2,5-oxadiazole) reacted with bromine by addition to give a4,5,6,7-tetrabromo adduct. Bromine in hydrobromic acid solution 4-brominated both 5-methyl- and 5-bromo-benzofurazans (74JHC8I3). When 4,7-dinitrobenzofurazan was treated with ammonium chloride in refluxing acetic acid, nucleophilic displacement gave rise to the 4-chloro-7-nitro derivative (83URP1004375). Naphtho[l, 2-c]furazans (42) are mainly 4-halogenated, but there is minor substitution in the 8-position (73CHE1331). 

Schemes Synthesis of 1,3,4-oxadiazoles using PS-BEMP and tosyl chloride...

The Ley group also investigated the PS-base/tosyl chloride methodology developed by Brain (see above. Scheme 8) for the synthesis of 2-aminooxadiazoles from semicarbazides, especially with a view to directly synthesize 2-aminosulfonamide substituted 1,3,4-oxadiazoles, a compound class of interest for agrochemical and pharmaceutical apphcations (Scheme 10) [71]. In this case, the choice of the supported base was crucial for the result of the reaction weak bases (PS-DIEA, PS-NMM) could still afford the cyclized 2-aminooxadiazole product, but could not efficiently... 

The initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

A modified literature procedure [10] provided a long-term high yield manufacturing process to the oxadiazole fragment, as depicted in Scheme 6.11. Amidation of tetrazole 40 with ethyl oxalyl chloride (41) afforded intermediate 42 which was... 

Scheme 6.11 Preparation of oxadiazole carbonyl chloride fragment 2.

Reaction of a perfluoroalkyltetrazole and a perfluoroacyl chloride yields, via a tetra-zolide and under elimination of nitrogen, the corresponding substituted oxadiazole [141]... 

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>. 

Rice and Nuss report that the Argopore MB-CHO polymer-supported amidoximes 282 (readily available from the nitrile 281), shown in Scheme 46, can be acylated with acid chlorides in the presence of excess pyridine to give the O-acylamidoximes 283. Cyclization was carried out with TBAF in THF at ambient temperature, to give the polymer-supported 1,2,4-oxadiazoles 284. Release of the 1,2,4-oxadiazoles 285 from the polymer support was achieved by treatment with 95% trifluoroacetic acid <2001BML753>. 

The reaction of hydroximoyl chlorides with the chiral, nonracemic hydrazones 313 (Equation 58) in the presence of TEA gave the 4,5-dihydro-l,2,4-oxadiazoles 314 as single diastereomers from which the chiral auxiliary was easily removed to furnish the corresponding 4-unsubstituted 4,5-dihydro-l,2,4-oxadiazoles with high ee s <1999H(50)995>. 

Aziridinylbenzaldoxime 340, formed from the reaction of a hydroximoyl chloride with aziridine 339 (Scheme 56), reacts with HG1 to form the chloroalkyl-substituted amidoxime 341. Reaction with sodium hydride affects ring closure to give the 3-aryl-4,5-dihydro-5-isopropyl-l,2,4-oxadiazoles 343. This latter reaction is proposed to proceed... 

The reaction of hydroximoyl chlorides 403 with amidoximes 402 in the presence of TEA leads to 1,2,4-oxadiazole 4-oxides 404 via 1,3-dipolar cycloaddition and elimination of an amine (Equation 77) <1997T1787, 2005JC0887>. 

Diazotization of 4-amino-l,2,5-oxadiazole-3-carbohydroximoyl chloride 132 gives 4-[chloro(hydroxyimino)-methyl]-l,2,5-oxadiazole-3-diazonium salt 133 (Scheme 35). Treatment of the latter with NaN3 afforded 4-azido-l,2,5-oxadiazole-3-carbohydroximoyl chloride 134 and the reaction with NaN02 yielded 2-cyano-2-hydro-xyiminoaceto-hydroximoyl chloride 135. By oxidation of 4-amino-l,2,5-oxadiazole-3-carbohydroximoyl azide 136... 

Dimerization of nitrile oxides derived from 4-amino- and 4-R-substituted l,2,5-oxadiazole-3-carbohydroximoyl chlorides 201 leads to the formation of tricyclic furoxans 200 or compound 202 (Scheme 45) <2001RJ01355>. 

Di-(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyl)-l,2,5-oxadiazole 2-oxide 306 was synthesized from D-mannose 305 by a route involving dimerization of mannopyranosyl nitrile oxide as the key step. Three methods were used for the generation of the nitrile oxide isocyanate-mediated dehydration of nitromethylmannose derivatives, treatment of aldoxime with aqueous hypochlorite, and base-induced dehydrochlorination of hydroximoyl chloride (Scheme 76) <2001TL4065, 2002T8505>. 

Glycosyl nitrile oxides 315, generated in situ by reaction of hydroxamoyl chlorides with DBU, participate in 1,3-dipolar cycloaddition with substituted alkenes leading to glycosyl isoxazolines the l,2,5-oxadiazole-2-oxides 316 are isolated as by-products in low yields (Scheme 79) <2004CHC353>. 

Acylation reactions of 2,5-bis(o-amino-phenyl)-1,3,4-oxadiazoles with an excess of chiral /V-tosyl-/-lcucyl chloride were performed in dry pyridine <2000JST109>. 

The Michael-type reaction of an anion (generated from compound 77) with ethyl crotonate yielded the corresponding ester 78 in 82% yield (Scheme 19). Alkylation of compound 77 with benzyl bromide afforded derivative 79 in 85% yield. The attempted reactions of the anion with oxiranes and trimethylsilyl chloride did not lead to the expected substitution products and the starting oxadiazoles were recovered in 70-80% yields <2001ARK101>. 

As in Section 5.06.9.1, the assignments are sometimes arbitrary. Important routes to oxadiazoles, aminooxadiazoles, oxadiazolinones, and oxadiazolinethiones involving the reaction of hydrazides RCONHNH2 with carboxylic acids, acyl chlorides, alkyl esters, or trialkyl orthoesters are described in Section 5.06.9.2.1, reactions with carbon disulfide... 

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