Oxadiazoles ketones

Any heterocycle containing the OCH=CH moiety can in principle extrude the superfluous fragment and form oxirene, as illustrated for a five-membered ring in Scheme 105. Probably the most propitious AB fragment would be nitrogen, but the required 1,2,3-oxadiazole (123) is unknown (see Chapter 4.21), probably because of ready valence tautomerization to diazoethanal (Scheme 106) (this approach has been spectacularly successful with the sulfur analogue of (2) (8UA486)). The use of (123) as an oxirene precursor is thus closely linked to the important diazo ketone decompositions discussed in Section 5.05.6.3.4(f). 

Polyfluoroalkyl- andperfluoroalkyl-substituted CO and CN multiple bonds as dipolarophiles. Dmzo alkanes are well known to react with carbonyl compounds, usually under very mild conditions, to give oxiranes and ketones The reaction has been interpreted as a nucleophilic attack of the diazo alkane on the carbonyl group to yield diazonium betaines or 1,2,3 oxadiazol 2 ines as reaction intermediates, which generally are too unstable to be isolated Aromatic diazo compounds react readily with partially fluorinated and perfluorinated ketones to give l,3,4-oxadiazol-3-ines m high yield At 25 °C and above, the aryloxa-diazolines lose nitrogen to give epoxides [111]... 

The reaction of 2-chloro-4,5-dihydroimidazole 347 with hydroxylamine-O-sulfonic acid gives 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate 348, which reacts with aldehydes and cyclic ketones to give the imidazo[l,2-f] fused 4,5-dihydro-l,2,4-oxadiazoles 350 (Scheme 58). Mechanistically, the reaction may be explained by the reaction of an imidazoline NH with the carbonyl followed by intramolecular electrophilic amination of the anionic oxygen present in the resultant intermediate 349 and elimination of the sulfate group <2003JOC4791>. 

Oxidative cyclization of acylhydrazones 110a, derived from aldehydes or ketones, with the use of lead tetraacetate (LTA) has been developed into a useful route to several disubstituted and tetrasubstituted oxadiazole derivatives 122, being a convenient source of relatively stable carbenes, like N(0)C , S(0)C , 0(0)C , or S(S)C <2000J(P1)2161 >. Some representative recent examples of the syntheses are collected in Table 2. 

N-methylcarbamate and N,N -dimethylcarbamates have been determined in soil samples by hydrolyses with sodium bicarbonate and the resulting amines reacted with 4-chloro-7-nitrobenzo-2,l,3-Oxadiazole in isobutyl methyl ketone solution to produce fluorescent derivatives [81]. These derivatives were separated by thin layer chromatography on silica gel G or alumina with tetrahydrofuran-chloroform (1 49) as solvent. The fluorescence is then measured in situ (excitation at 436 nm, emission at 528 and 537nm for the derivatives of methylamine and dimethylamine respectively). The... 

In a related study, it has been shown that several aldehyde N-acylhydra-zones undergo oxidative cyclization with IBD in methanolic sodium acetate to give 2,5-disubstituted 1,3,4-oxadiazoles (Eq. 32). The oxidation of ketone N-acylhydrazones by IBD in methanol or ethanol affords the corresponding 2-alkoxy-A -l,3,4-oxadiazolines in excellent yields (Eq. 33), while oxidative cyclization of acetone 4-phenylsemicarbazone provides 2-(A -phenylimino)-A -l,3,4-oxadiazoline in 93% yield (Eq. 34) (93JOC3381). 

Some rearrangements in the 1,3,4-oxadiazole series are explained by an /pso-nucleophilic attack by the side-chain (Scheme 72). Thus, under amination conditions, oxadiazolyl ketones 458 give the rearranged thia-zoles 460 via the enamino compounds 459 as intermediates. Sometimes, performing the reaction in refluxing acetic acid causes direct cyclodehydration into thiazolo[2,3-c]-s-triazoles. In a similar way, hydrazine in refluxing acetic acid converts compounds 458 into triazolo(3,4-b)thiadiazines 463... 

The 5-methyl-3-phenyl-l,2,4-oxadiazole (84) is deprotonated by bases to an anion, which adds to the carbonyl group of ketones or of CO2 (Scheme 31) <89JCS(Pl)2047>. In contrast, the methyl group of (85) is not lithiated by butyllithium. Instead, the reagent adds to the 4,5-bond (Equation (19)) <70CJC2006>. 

A general method for the preparation of 4,5-dihydro-1,2,4-oxadiazoles(171) involves the condensation of amidoximes with aldehydes or ketones, or azomethines <84UKZ515>, a reaction invented by Tiemann <1889CB2412, 87JHC101, 90H(31)233, 93AP(326)383>. The reaction is reversible on treatment with aqueous acid the hemiaminals (171) are hydrolyzed to the carbonyl compounds and (96) (Scheme 75). 

Acyl substituents at the 3- and/or 4-positions result in decreased hydrolytic stability compared with the alkyl and aryl derivatives described above. Despite this constraint most of the usual reactions of the carbonyl group are possible. Aldehydes <9ILA1211> and ketones are oxidized to the carboxylic acid, borohydride reduction affords the expected alcohols, and epoxides are formed on reaction with diazomethane. Oximes and arylhydrazones are formed with hydroxylamine and arylhydrazines, and the products may subsequently undergo monocyclic rearrangement involving the oxadiazole to give the corresponding isomeric furazans and 1,2,3-triazoles (Section 4.05.5.1.4). 

Werden cc-(Ethoxycarbouylamino)-ketone (R2 = OC2H5) als Acyl-Komponente eingesetzt, so erhalt man unter Abspaltung von Ethanol 5-Hydroxy-l, 2,4-oxadiazole. 

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... 

The oxidation of oximes of oj//-perfluoroaldehydes with fuming nitric acid gives furoxane derivatives, e.g. the preparation of 3,4-bis(8//-hexadecafluoro)-l,2,5-oxadiazole (V-oxide (9).128 The conversion of ketone oximes to nitro compounds is of practical importance. Hexa-fluoroacetone oxime is transformed into l,l,l,3,3,3-hexafluoro-2-nitropropane (10) using dinitrogen pentoxide liberated in situ.249... 

A methylene group between the oxadiazole ring and a carboxyl group acts like a malonic acid with respect to ease of loss of the carboxyl group. Likewise the acetyl group from an acetonyl side chain at C-5 is lost in basic solution, analogous to the ketone split in a fi-keto ester or / -diketone. This was recognized in the early work on oxadiazoles by Tiemann,48 Wiese,49 Richter,47 and Schubart.50... 

The iron-catalyzed [3 + 2]-cycloaddition (Huisgen reaction) of nitriles and carbonyl compounds as reported by Itoh et al. is one of the rare examples reported where an iron reagent can be utilized for the synthesis of 1,2,4-oxadiazoles (Scheme 9.35) [93]. In this reaction, methyl ketones are nitrated at the a-position by Fe(N03)3 to generate an a-nitro ketone. This intermediate rearranges to an acyl cyanate, which reacts further with the nitrile to give the heterocyclic product 48 in good to excellent yields (R1 = Ph, R2 = CH3 95% yield). 

Thiadiazolidines can be obtained from aliphatic aldehydes or ketones and disubstituted hydrazine derivatives (Scheme 29). A typical preparation of a mesoionic compound consists in the reaction of 1-methylthioacylhydrazine and phosgene (Scheme 31a). Syntheses by three-bond formation are rare for example, a one-pot reaction of an aldehyde with hydrazine and sulfur. A typical ring transformation reaction is the irradiation of 1,3,4-oxadiazoles to yield 1,3,4-thiadiazoles. 

Examples include the synthesis of 3-amino-l,2,4-oxadiazoles starting from 3-acylamino-5-methyl-l,2,4-oxadiazole <2002H811> and 2-aryl-l,2,3-triazoles from l,2,4-oxadiazole-3-ketone arylhydrazones <1999T12885, 2006JOC5616>. Oximes, hydrazones, formamidines, and thioureas of the furazan series also undergo base-catalyzed mononuclear rearrangements <2004RCB1121>. Nucleophilic attack at N(3) takes place in the benzofuroxan series. For example, reaction with secondary amines leads to o-nitroarylhydrazines (Scheme 55). 

Furan 2-Amino-4-butylimino-5-ethyl-5-methyl-4,5-dihydro-E15/2, 1810 [R2C(OH)-C = C —CN + R-NH2] 2-Hexensaure 2-tert.-Butylamino-3-methoxy- -nitril E15/2, 1277 [R-CH(OR)2 + R-NC] 1,2,4-Oxadiazol 5-Methyl-3-octyl-E8c, 422 [H,7C8-C(NH2) = N-OH + (H3C-C0)20] 2-Pentensaure 2-tert.-Butylamino-3-meihoxy-4-methyl- -nitril E15/2, 1277 [R-CH(OR)2 + R-NC] Pyrrolidin (+ )-(5> I -Cyclopentyli-denamino-2-(methoxy-methyl)-E14b, 489 E21a, 997 (aus Keton)... 

There is one example in which part of the amidine system is a C—N bond in a heterocyclic ring. The enamino ketone condensation products (42) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds cyclize in basic medium to form 60-80% yields of imidazoles. The driving force for this reaction is provided by the well-established, general attack of a nucleophilic centre in the side-chain at N-2 of the heterocyclic ring, but it is unusual in that a carbon nucleophile (rather than an oxygen or nitrogen species) is implicated (Scheme 23). 

Dehydrative cyclization of 3-(5-carboxy)-5-phenyl-4-(pyrrol-l-yI)l,2,4-triazole (508) with poly phosphoric acid gave (82G345) the 1,2,4-triazolo[3,4-/7]l,3,4-thiadiazine (509). Ring transformation of 1,3,4-oxadiazoles to 7//-l,2,4-triazolo[3,4-/>]l,3,4-thiadiazines (507) was reported by Sasaki et al. (82JOC2757) through the reaction of [(1,3,4-oxadiazol-2-yl)thio]ketones (123) with hydrazine hydrate in the presence of acetic acid. 

Indirect oxidation with tris-(4-bromophenyl)amine or 2,3-dihydro-2,2-dimethylphe-nothiazine-6(l/7)-one transforms formazane to tetrazolium, semicarbazones to 2-amino-1,3,4-oxadiazoles, benzaldehyde 2-pyridylhydrazones to 5-triazolo[4,3-a]pyridinium compounds, and phenyl 2-pyridyl ketone phenylhydrazone to 1/7-1,2,3-triazolo[3,4-a]-pyridi-nium compounds [123]. 

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