Amidoximes, acidity

Beckmann rearrangement of amidoximes to urea derivatives in the presence ol acids (benaene suMonyl chloride). 

Amino-4-cyanofurazan has been prepared by treatment of amidoxime 77 with Pb02 in acetic acid (94CHE608, 94KGS693) (Scheme 43). 

To this mixture, under continuous stirring and controlling of the reaction temperature to remain beyond 15°C, there is slowly added (3-chloropropionyl chloride. After addition of the acid chloride, stirring is continued for a further hour. Then with cooling there is added portionwise a small amount of water. Further amounts of water are introduced into the reaction mixture and the chloroform solution containing the /3-chloropropionyl a-ethylbenz-amidoxime is separated. 

In 2005, a group of researchers at Abbott turned their attention to the synthesis of a different regioisomer, the 1,2,4-oxadiazoles [75]. These heterocycles are normally prepared by reaction (mediated by a couphng reagent) of a carboxyhc acid with an amidoxime, followed by based-catalyzed cychzation at high temperature (Scheme 11). 

An alternative reported in the same publication involves the in situ conversion of the carboxylic acids to the corresponding acyl chlorides using PS-PPh3 and CCI3CN (THE, 10 °C, 5 min) before treatment with the amidoxime in the presence of DIEA (THE, 150 °C, 15 min). The resin-bound phosphine not interfering with the second step, and THF being the best solvent for both steps, the two-steps sequence could be performed one-pot with yields comparable to those obtained using the HBTU/PS-BEMP combination (Scheme 12). 

Scheme 12 Synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using PS-reagents...

Oxadiazoles are synthesized by the reaction of an amidoxime with the imidazolide of a carboxylic acid. 

The cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

Ring syntheses of 1,2,4-oxadiazoles from a one-atom component and a four-atom component 5.04.9.1,2(i) Syntheses from amidoximes and carboxylic acids and their derivatives... 

The reaction of an amidoxime 206, the four-atom component N-C-N-O, with a carboxylic acid derivative constitutes the historically most used <1984CHEC(6)365, 1996CHEC-II(4)179> entry into the 1,2,4-oxadiazole nucleus, and this approach has continued to be popular since it was reviewed in CHEC-II(1996). The reactions discussed in this section proceed, as discussed in Section 5.04.9.l.l(iii) (see also Scheme 30), via a nonisolable acylated amidoxime. 

Table 4 1,2,4-Oxadiazoles available from the reaction of carboxylic acids with amidoximes in the presence of an activator (see Equation 32)... 

Rz (carboxylic acid) Rl (amidoxime) Activating agent Yield /207 (%) References... 

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

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 conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

As Equation (54) shows, N-substituted amidoximes 306 will also react with either formaldehyde or acetaldehyde to give the 4,5-dihydro-l,2,4-oxadiazoles 307. Acetaldehyde required the presence of acetic acid, whereas the use of formaldehyde allowed the reaction to proceed in the absence of acid <1998EJM715>. 

Addition of ammonia as a model nucleophile to nitrile oxides was studied by a semiempirical MNDO method, for fulminic acid and acetonitrile oxide (121). The reaction is exothermic and proceeds in two steps. The first (and rate-determining) step is the formation of a zwitterionic structure as intermediate. The second step, which involves transfer of a proton, is very fast and leads to the formation of Z-amidoximes in accordance with experimental data. Similar results were... 

Formic acid, Palladium-carbon catalyst, 0418 Formic acid, Phosphorus pentaoxide, 0418 Furan-2-amidoxime, 1872... 

The steps were initially followed in order to optimize the conditions. In the preliminary experiments, the conversions to amidoximes (first step) were complete within 6 min at 150°C. The second step, cyclization to the final product, was finished after 10 min at 200°C and 7.5-9.0 bar. The stream of the intermediate amidoxime needed to be cooled before the reaction with the acid chloride, and this is achieved by introducing a cooling loop at 0°C. 

The main group of methods for the preparation of a 1,2,4-oxadiazole ring is based on cyclization of amidoxime derivatives in the presence of acylating agents °. A surprisingly easy cyclization of O-benzoyl-/ -piperidinopropioamidoxime 247 to oxadiazole 248 in DMSO at room temperature was described (equation 107) . 3-(3-Aryl-1,2,4-oxadiazol-5-yl)propionic acids 250 were obtained by the reaction of amidoximes 249 with succinic anhydride under microwave irradiation or conventional heating (equation 108) °°. 

Reaction of amidoximes 286 with boronic acids in refluxing toluene leads to 1,3,5,2-oxadiazaboroles 287 in yields up to 95% (equation 123). ... 

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... 

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