Amidoximes 1.2.4- oxadiazoles

Amidines, N-(l,2,4-thiadiazol-5-yl)-, rearrangement, 56, 103 Amidoximes, 1,2,4-oxadiazol-3-yl-, rearrangements, 56, 55 Amidyl radicals, see Radicals, nitrogen Amination, asymmetric, of carboxylic acids by chiral nitroso compds, 57, 41 Amines, catalysis of 3-acyl-1,2,4-oxadiazole arylhydrazone rearrangement by, 56, 87 Amines, thionitroso-, formation, 55, 20 Aminium cation radicals, see Radicals, nitrogen... 

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). 

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 reduction of the Wang resin-bound 1,2,4-oxadiazole 107 (Equation 15) with LiAlH4 resulted in reductive cleavage from the resin and a reductive ring opening of the 1,2,4-oxadiazole to furnish the amidoxime 108 <1999BML2101>. 

As detailed in CHEC-II(1996) <1996CHEG-II(4)179>, 4,5-dihydro-l,2,4-oxadiazol-5-ones are readily hydrolyzed, and further examples (see Equation 17) of this transformation have been reported involving the synthesis of amidoximes 126 from the dihydro-1,2,4-oxadiazol-5-one 115 <2004T10907>. 

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)... 

The reaction of malonates 213 with 2equiv of an amidoxime in the presence of potassium carbonate results in the formation of the bis-l,2,4-oxadiazoles 214 (Equation 35), a process that also gives excellent yields of the mono-1,2,4-oxadiazoles when a 1 1 ratio is employed (see Table 5) <2006TL3629>. 

The reaction of the stable and readily available N-protected (a-aminoacyl)benzotriazoles 215 (Equation 36) with amidoximes 206 in ethanol gave the N-protected 5-amino-substituted 1,2,4-oxadiazoles 216 in high yield, under mild conditions and with good (>97%) retention of chirality <2005ARK36>. The method is also applicable to aromatic (V-acylbenzotriazoles, giving access to 5-aryl-l,2,4-oxadiazoles in 73-82% yield. 

The imidocarbonylchlorides 218 (Equation 39) react with amidoximes in chloroform in the presence of DBU to give the 5-anilino-l,2,4-oxadiazoles 219 <2001JPES60>. 

Young and DeVita have shown that 1,2,4-oxadiazoles can be prepared by a new route in a novel one-pot procedure by the palladium-mediated coupling of an aryl iodide with an amidoxime in the presence of carbon monoxide (Equation 40) <1998TL3931>. 

As part of a later investigation into palladium-catalyzed reactions of diaryliodonium salts 220, Chen and Zhou found that reaction with amidoximes in the presence of carbon monoxide also gave 1,2,4-oxadiazoles (Equation 41) <2002SC887>. 

Microwave irradiation of amidoximes in the presence of an aldehydes under solvent-free conditions has been reported to give fully conjugated 1,2,4-oxadiazoles directly, a process that is notable because the amidoximes can be prepared in the same reaction vessel from a nitrile and hydroxylamine (Scheme 33) <2006TL2965>. 

The cycloaddition of nitrile oxides to amidoximes 234 leads to 1,2,4-oxadiazole 4-oxides which can then be deoxygenated with trimethyl phosphite (Equation 48) <1997T1787>. 

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>. 

Each of the routes discussed thus far in this section are reliant upon amidoxime-based methods. In a change from this paradigm, Makara etal. produced the polymer-supported benzotriazoles 294 and converted them easily into the iV-acyl-177-benzotriazole 1-carboximidamides 295. Cyclization with hydroxylamine gave the supported 3-amino-l,2,4-oxadia-zoles 296 which were cleaved with TFA to give the free 3-amino-l,2,4-oxadiazoles 297 (Scheme 49) <2002TL5043>. 

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>. 

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>. 

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) °°. 

Oxadiazoles can be sucessfully obtained from amidoximes and diethyl carbonate/ f-BuOK °, triethyl orthoformate/BFs OEtg or by reaction of hydroximoyl chlorides with nitriles . ... 

It has been found that 1,2,4-oxadiazoles 255 can be obtained from amidoximes 254 and aryl iodides by the palladium-mediated reaction in the presence of carbon monooxide. This reaction was applicable to both electron rich and deficient aryl iodides (equation 110) °. Amidoximes in the system Arl+ Ph X /CO/PdCH/KiCOs/NMP/tolnene also afforded 5 -aryl-1,2,4-oxadiazoles. ... 

Phenyl-5-bromodifluoromethyl-l,2,4-oxadiazole was obtained in the system PhC(=NOH)NH2/BrCF2COOEt/Et3N/toluene ". 1,2,4-Oxadiazoles can be also successfully obtained from amidoximes linked to solid resin and (C1CH2C0)20 in 2-methoxyethyl ether (MeOCH2CH2)203 ... 

Trifluoromethyl-l,2,4-oxadiazoles are hydrolyzed to amidoximes when treated at ambient temperature with ammonia in ethanol/water <91KGS827>. 

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>. 

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