1.2.4- Oxadiazole-3-carboxylates

Oxadiazole-3-carboxylic acid, 5-methoxy-methyl ester... 

Carboxylic acid hydiazides are prepared from aqueous hydrazine and tfie carboxylic acid, ester, amide, anhydride, or halide. The reaction usually goes poody with the free acid. Esters are generally satisfactory. Acyl halides are particularly reactive, even at room temperature, and form the diacyl derivatives (22), which easily undergo thermal dehydration to 1,3,4-oxadiazoles (23). Diesters give dihydtazides (24) and polyesters such as polyacrylates yield a polyhydrazide (25). The chemistry of carboxyhc hydrazides has been reviewed (83,84). 

A similar intramolecular trapping of the intermediate (511) from the photolysis of the corresponding methyl tetrazole-l,5-dicarboxylate (510) gave methyl 5-methoxy-l,2,4-oxadiazole-3-carboxylate (512). 

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

The original route for the synthesis of potassium 5-methyl-l,3,4-oxadiazole-2-carboxylate (39) via an intramolecular condensation of ethyl (2-acetylhydrazinyl)-(oxo)acetate (37) suffered from moderate yields (Scheme 6.10). 

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

Monaca et al. (2003) examined the effect of the SSRI citalopram on REMS in 5-HTia and 5-HTib knockout mice. Citalopram suppressed REMS in wild-type and 5-HTib mice but not in 5-HT,A I mutants. The 5-HTja receptor antagonist WAY 100635 prevented the citalopram-induced inhibition of REMS in wild-type and 5-HTib knockout mice. However, pretreatment with the 5-HTib receptor antagonist GR 127935 [2 -methyl-4 -(5-methyl-(l,2,4)oxadiazol-3-yl)-biphenyl-4-carboxylic acid ((4-methoxy-piperazine-l-yl)-phenyl)amide] was ineffective in this respect. It was concluded that the action of citalopram on REMS in the mouse depends exclusively on the activation of 5-HT,A receptors. Notwithstanding this, there is unequivocal evidence showing that administration of selective 5-HTib receptor agonists suppresses REMS in the rat. 

A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc cluster Zn4(0C0CF3)60 as catalyst, essential for condensation and cyclodehydration reactions. For example, the use of (5)-valinol allowed the easy synthesis of oxazolines 125 and 126 in satisfactory yields <06CC2711>. A one-pot direct preparation of various 2-substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent <06TL6497>. 

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)... 

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>. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

As in Section 5.06.9.1, the assignments are sometimes arbitrary. Important routes to oxadiazoles, aminooxadiazoles, oxadiazolinones, and oxadiazolinethiones involving the reaction of hydrazides RCONHNH2 with carboxylic acids, acyl chlorides, alkyl esters, or trialkyl orthoesters are described in Section 5.06.9.2.1, reactions with carbon disulfide... 

The reactions of hydrazides with the respective carboxylic acids afforded oxadiazole derivatives 123 <1996JME2753>, 124 <2000BML1645>, 125 <2003JFC163>, and 126 <2004EJM535>. The reactions... 

Potassium 4-hydroxy-5,7-dinitro-4,5-dihydrobenzofurazanide 3-oxide, 2114 Potassium 3-methylfurazan-4-carboxylate 2-oxide, 1415 4a,5,7a,8-Tetrahydro-4,8-methano-4A-indeno[5,6-c]-l,2,5-oxadiazole 1- and 3-oxide, 3282... 

AUtyl 2-(substituted cinnamoylamino)-3-dimethylaminopropenoates 251 are transformed to Ai-cinnamoyloxalic acid hydroxyimidic amides 252 by treatment with sodium nitrite in aqueous HCl at 0°C. The latter can be further transformed into substituted 5-styryl-l,2,4-oxadiazole-3-carboxylates 253 by standing in aqueous HCl at room temperature (equation 109) ° . 

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