1.2.4- Oxadiazoles from amidoximes

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

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... 

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 ... 

In contrast, the oxidation of oxadiazolines (method S) can be used to synthesize oxadiazoles from aromatic amidoximes and aliphatic aldehydes. 

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). 

Oxadiazole 4-oxides 157 (Ar, Ai = Ph or/ -Tol) are formed from amidoximes 155 and nitrile oxides 156 <97X1089, 97T1787>. l,2,4-Oxadiazolidine-3,5-dione 158 is benzylated at N-2 by benzyl bromide <97SL263>. 3,6-Dimethylpyridazinol4,5-c]furoxan 159 is converted into 3-acetyl-4-(l,l-dinitroethyl)furoxan 160 by the action of nitric acid <96ZOR957>. 

Oxadiazoles and 1,2,4-oxadiazoles are heterocyclic aromatic compounds that appear in many bioactive molecules. Previous methods for the synthesis of 1,2,4-oxadiazoles include the coupling of amidoximes with carboxylic acid derivatives, aerobic C—H oxygenation of amidoximes, or a cyclization of nitrile oxides to nitriles. Telvekar and Takale developed the preparation of 1,2,4-oxadiazoles from substituted diketone derivatives through a Beckmann rearrangement process tScheme S.3S1. When treated with diphosphorus tetraiodide in dichloromethane at room temperature, dioximes 150 formed the Beckmann products, 1,2,4-oxadiazoles 151, in excellent yields. 

Disubstituted 1,2,4-oxadiazoles 6 are conveniently prepared from amidoximes (accessible from nitriles by addition of hydroxylamine to the CN-triple bond) by cyclocondensation with esters, likewise with acid chlorides or nitriles [463] ... 

Similarly, 3-benzoyl- 24 (R=Ph) [15] and 3-carboxyethyl-5-perfluoroalkyl-oxadiazole 24 (R=OEt) are prepared from amidoximes (23 R=Ph, OEt respectively) and the corresponding perfluoroalkanoyl chlorides (or anhydrides) (Scheme 6). 

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. 

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

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>. 

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>. 

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 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... 

A synthesis of 5-unsubstituted 3-aryl-1,2,4-oxadiazoles starts from easily accessible A-(dicyano-vinyl)amidoximes (Schemes 61, 62) <86JAN111,94H(38)113>. 

The first examples of furazan and furoxan nitrile oxides have been reported in the early 1990s. 4-Aminofurazan-3-carbonitrile oxide (65) was generated from the hydroximoyl chloride with base and its cycloaddition reactions investigated <92KGS687>, and the 4-phenyl analogue (66) is formed via the nitrolic acid derivative by treatment of the aldoxime with dinitrogen tetroxide <93LA44i>. Furazan-3-amidoximes react in the usual way with nitriles to yield 3-(furazan-3-yl)-1,2,4-oxadiazoles <9013941 >. 

In methods C through G, oxadiazoles are formed from unstable N-acylamidoximes but the starting materials from which the unisolable intermediates are produced, are not amidoximes. Except for method C which is general, methods D, E, F, G lead to particular compoimds containing a functional group as substituent. 

In contrast with the classical synthesis, this reaction occurs in one step, in the absence of a solvent and the formed oxadiazole is easily isolated from the other reaction products. Even in the case of non- or mono-substituted oxadiazoles, the new reaction affords comparable or improved 3delds. The process is quite general. It concerns all kinds of amides and amidoxime salts and is generally carried out at the melting point of the mixture (100—200° C). 

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