Amidoximes, condensation with

The interaction of amidoximes (96) with nitrites in the presence of ZnCl2 and HCl affords 1,2,4-oxadiazoles (Scheme 38) <9073941, 94izvil8>. The activation volumes for cyclocondensations of benzamidoxime with benzonitrile and acetonitrile are negative (—14.6 mL mol, —18.5 mL mol respectively). Thus, pressure accelerates the condensation <87NKK1807>. 

Amidoximes readily condense with aliphatic aldehydes in aqueous solution to form 4,5-dihydro-l,2,4-oxadiazoles (oxadiazolines). 

Amidoximes (46) were first used as a source of 1,2,4-thiadiazoles in 1889 their condensation with carbon disulfide or with an excess of aryl isothiocyanate yields 3-aryl-5-mercapto- (47)6 -73 or 3-aryl-5-aryl-amino- 1,2,4-thiadiazoles (50),71,74,75 respectively. The latter reaction has been reexamined and discussed by Gheorgiu and Barbos76 who suggest that an initial addition of two moles of phenyl isothiocyanate to one of benzamidoxime is followed by cyclization of the intermediate (49), with elimination of phenylthiocarbamic acid (51). Decomposition of the latter gives rise to the by-products observed (cf. following scheme). 

Two complementary methodologies were designed for rapid generation of libraries of 3,5-disubstituted 1,2,4-oxadiazoles from widely available carboxylic acids and amidoximes [93]. Both methods employed solid-phase reagents to simplify the purification process. Carboxylic acids were directly condensed with amidoximes in the presence of HBTU and an excess of PS-BEMP in acetonitrile (150 °C, 15 min). Alternatively, carboxylic acids were in situ converted to acid chlorides (with PS - PPI13/CCI3CN in THF) and subsequently reacted with amidoximes to furnish disubstituted oxadiazoles in good to excellent yields (Scheme 33). 

When aldehydes condense with 2-amino-2-phenylacet-amidoxime (23) derivatives of 5-aminoimidazole (24) are formed in high ( 80%) yield.112... 

The first A/ -oxides of the 1,2,4-thiadiazole ring system have been reported and were prepared by condensation of benzamidoximes (86) with 4,5-dichloro-l,2,3-dithiazohum chloride (87). A -labelling showed the compounds to be 4-oxides (88) and a mechanism was proposed for their formation. Alkyl amidoximes and arylamidoximes with electron-withdrawing substituents did not give A/ -oxides, but only the dithiazolone (89) and the dithiazolthione (90) <96CC1273>. 

Condensation of diazonium salts 1152 with activated nitriles provides hydrazones 1153. Treatment of hydrazones 1153 with hydroxylamine affords amidoximes 1154 in high yield. Upon heating with anhydrous sodium acetate in refluxing DMF, compounds 1154 undergo intramolecular cyclocondensation to provide 5-substituted 4-amino-2-aryl-277-1,2,3-triazoles 1155 in 75-85% yield (Scheme 190) <2006ARK(xv)53>. 

However, with liquid ammonia or anhydrous methylamine 1,2,4-oxadiazines (88) are formed. 5-(Chloromethyl)-l,2,4-oxadiazoles (e.g., (86) react with urotropin to form salts, which are hydrolyzed with hydrochloric acid to 5-(aminomethyl) compounds (the Delepine reaction). Alternatively, 5-(aminomethyl)-l,2,4-oxadiazoles have been prepared by condensation of amidoximes with a-amino-acids <72JHC435>. 

The unsubstituted 1,2,4-oxadiazole has been prepared from formamidoxime and the mixed anhydride of acetic and formic acid, or formamide <67BSB92>. 5-Unsubstituted 1,2,4-oxadiazoles are formed by heating the condensation products of amide oximes with formic acid <63CI(M)1238>. Alternatively, amidoximes are treated with triethyl orthoformate in the presence or absence of... 

Thermal condensation of a-chlorocarboxylic chlorides with amidoximes affords 1,2,4-oxadiazoles. However, in the presence of a strong base (NaH) l,2,4-oxadiazin-5-ones were isolated (Scheme 41) <87H(26)163>. 

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). 

Sheradsky has found that the hydroxyl function of a ketoxime such as acetophenone oxime can be made to react with DMAD when the reaction is carried out in methanol with a basic catalyst, to give mixture of the fumarate and maleate isomers (164) in the ratio 2 1. This mixture on heating undergoes a hetero-Cope rearrangement followed by cyclization and dehydration to give dimethyl 5-phenylpyrrole-2,3-dicarboxylate (168) (Scheme 25). Similarly, Heindel and Chun have reported that vinyl ether adducts (171), obtained by the condensation of arylamide oximes with DMAD, get thermally converted into oxa-diazolines (172) or imidazolinones (174), depending on the reaction conditions. A similar reaction occurs with aromatic amidoxime-methyl propiolate adducts to give imidazoles (170) (Scheme 26). 1,2,4-Dioxazoles have been reported to be formed in the reaction of hydrox-amic acids with DMAD. - ... 

The condensation of amidoximes with the appropriate reagents described in methods H, K and L occurs in one step. As no intermediate is isolated, the reaction mechanism is not clearly established but an acylation of amidoximes may be postulated. 

An efficient solvent-free synthesis of 1,2,4-oxadiazoles 235 was described using microwave irradiation by reaction of acyl chlorides with amidoximes <03H(60)2287>. The same kind of condensation was used for the synthesis of unnatural p and a-amino acids, 237 and 239 respectively, with an oxadiazole nucleus, using different derivatives of aspartic acid... 

Attempts to prepare AH-1,2,4-oxadiazin-6(5//)-ones by base (NaH in THF)-induced condensation of amidoximes with chloroethanoyl chlorides have failed only the isomeric 5(6//)-ones (205) are obtained <87H(26)163,92SC209). The reaction is of mechanistic interest in that the 0-acylated oximes... 

Formation of 1,2,4-oxadiazines occurs by acid-catalyzed ring expansion of a-aziridino oximes and dioximes, and by 1,3-dipolar cycloaddition of arylcarbonitrile oxides and 2-acyl-2//-azirines (Section 6.14.10). Preparation of l,2,4-oxadiazin-5-ones can be achieved by ring closure of A-carboxymethyl and A-alkoxycarbonylmethyl amidoximes (Section 6.14.9.1.1), by the acid-catalyzed condensation of arylaldehydes with O-alkyl-A-acylhydroxylamines (Section 6.14.9.2.3.1), and by reaction of A-hydroxyureas or amidoximes with a two-carbon fragment such as an a-halo ester or an acyl halide (Section 6.14.9.2.2.1). 

Scheme 6.17 Preparation of 1,2,4-oxadiazoles via condensation of amidoximes with carboxylic acids under the irradiation of microwave...

On the other hand, 1,2,4-oxadiazole derivatives could be prepared efficiently by the condensation of amidoximes with carboxylic acids in the presence of one equivalent of (9-(benzotriazol-l-yl)-Af,Af,X,X-tetramethyluronium hexafluorophosphate (HBTU) and three equivalents of PS-BEMP under microwave irradiation [70] (Scheme 6.17). This method is highly desirable in an automated format where most of the reagents can be added through liquid-delivery lines, and the PS-BEMP reagent can be easily removed by filtration upon completion of the reaction. 

The oxadiazole 140, related to ribavirin, has been prepared by cyclization of a known sugar-protected amidoxime. The 4 -thio-analogues 141 (X = O, S) of furanfurin and thiophenfurin (Vol. 29, p. 283), themselves analogues of ribavirin, have been prepared by condensation between the heterocycles, as their ethyl esters, with 0-protected derivatives of 4 -thioribofuranosyl acetate. The thiophene compound ( thiophenthiofurin ) had cytotoxicity towards cancer cell lines, but less so than thiophenfurin. A previously-known 2,5-anhydroglucose derivative 142 has been converted to the pyrazole 143, and some related compounds. Some pyrazole iso-C-nucleosides are mentioned in Chapter 2. Various 3-cyano-2-(P-D-ribofuranosyl)-1,5-benzodiazepines have been prepared by a novel ring transformation of 5-(tri-0-benzoyl-p-D-ribofuranosyl)isoxazole-4-carbaldehyde. ... 

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