1.2.4- Oxadiazoles amides

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). 

From a medicinal chemist s point of view, oxadiazoles are among the most important heterocycles as they are one of the most commonly used bioisosters for amide and ester groups [67]. As such it is hardly surprising that the two regioisomeric oxadiazole scaffolds received the most interest in the field of microwave-assisted synthesis using polymer-supported reagents. 

In an attempt to identify compounds with better pharmacokinetic properties, the amide group was replaced by ester [96], oxadiazole and... 

The initial retrosynthetic analysis of 1 resulted in the cleavage of the two amide bonds and a C-N bond leading to the four components oxadiazole carbonyl chloride 2, methyl iodide, 4-fluorobenzylamine (4-FBA) and the densely functionalized hydroxypyrimidinone 3 (Scheme 6.1). These synthetic disconnections were reasonable and should be applicable for long term route development. 

Amidation with 4-FBA prior to installing oxadiazole carboxamide. 

Amidation with 4-FBA Prior to Installing the Oxadiazole Carboxamide... 

The Medicinal Chemistry route introduced the oxadiazole fragment prior to installation of the 4-FBA (Scheme 6.1). The overall yield for these two steps was only 37%. The oxadiazole required a two-step synthesis and was a much more expensive reagent than 4-FBA. In order to improve the chemical yield, reduce cost and improve the overall process robustness, we investigated the amidation with 4-FBA prior to installing the oxadiazole moiety. 

A modified literature procedure [10] provided a long-term high yield manufacturing process to the oxadiazole fragment, as depicted in Scheme 6.11. Amidation of tetrazole 40 with ethyl oxalyl chloride (41) afforded intermediate 42 which was... 

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. 

Recently, Kraft and Osterod [157] reported the synthesis of poly(aramide) dendrimers possessing either electron-deficient 1,3,4-oxadiazole (70) or aromatic systems (71) linked by amide units to a central triphenylmethane unit (Fig. 31). 

Standard transformations at the a-carbon, as discussed in CHEC-II(1996) <1996CHEC-II(4)179>, proceed without incident. Selected recent examples (Scheme 19 Equation 22) include the conversion of the esters 153 into the hydrazides 154 and thence into the methylene carbohydrazides 155 <2005HC029>, a process that has been shown by the same workers to apply to other aldehydes (benzaldehyde, 4-A Ar-dimethylaminobenzaldehyde, furfuralde-hyde, or thiophene 2-carboxaldehyde) with equal success <1999FES747>, and the conversion of the ester 156 into amide 157 <2005NN1919>, a process that demonstrates the robustness of the 1,2,4-oxadiazole ring. 

The polymer-supported 5-chloromethyl-l,2,4-oxadiazole 162 undergoes easy reaction with primary amines to give the 5-aminomethyl oxadiazoles 163, which serve as excellent substrates for the synthesis of amides or sulfonamides 164 (Scheme 21 - yields not reported) <1999TL8547>. 

Oxadiazole amine 174 serves as an excellent template for the introduction of a wide variety of 5-amido side chains onto the 1,2,4-oxadiazole nucleus (Equation 26), and several such products 175 are potent inhibitors of the tyrosine kinase ZAP-70 <1999BML3009>. Amide or pseudopeptide side chains can also be introduced by the... 

The intermediate acylamidine 244 functions as the three-atom component in reaction with hydroxylamine to give the [l,2,4-oxadiazol-5-yl]pyrazole 245, where the intermediate acylamidine 244 was obtained in good yield from reaction of the corresponding amide 243 with dimethylacetamide-dimethyl acetal (Scheme 37) <1999JME2218>. 

If trivalent phosphoms compounds are to be treated as electron-deficient species, then reactions of oxadiazoles with some Lewis acids should be reported here. 2-Phenyl-l,3,4-oxadiazole reacting with phosphoms trichloride in pyridine solution in the presence of triethylamine at low temperature furnished the respective dichlorophosphine and chlorophosphine, which were trapped by dimethylamine to give the corresponding amides. 2-Phenyl-l,3,4-oxadiazole also interacts over 24 h with the less reactive chlorodiphenylphosphine and dichlorophenylphosphine at room temperature to give phosphines (Scheme 14) <1999CHE1117>. These reactions of oxadiazoles resemble the behavior of 1-alkylimidazoles toward trivalent phosphorus derivatives. 

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. 

Dendrimers, which contain an electron-deficient 1,3,4-oxadiazole ring and aromatic systems linked by amide units to triphenylmethane core, were synthesized (Scheme 16) <1997CC1435>. 

With phenyllithium, the iminophosphoranes of benzoic acid hydrazides 157 can be deprotonated, as shown in Scheme 62.0-Acylation of the amide-enolates 158 affords intermediates 159, which are in turn cyclized by an aza-Wittig reaction to 1,3,4-oxadiazoles 160 (68JA5626). 

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) ° . 

It is noteworthy that 4,5-dihydro-1,2,4-oxadiazoles with a nucleophilic j6-aminoethyl substituent in the 3-position undergo ring transformation to cyclic amide oximes (48) by nucleophilic attack on C(5) (Scheme 17) <92JCS(Pi)3069>. 

Dihydro-1,2,4-oxadiazol-5-ones (74) cannot be 7V-acylated by either chlorocarbonyl isocyanate or trichloroacetyl chloride. However, preparation of 4-chlorocarbonyl compounds (73) can be achieved by cycloaddition of stable nitrile oxides to the C=N double bond of chlorocarbonyl isocyanate <888994, 90ZOR339). Compounds (73) decompose with ammonia, primary amines, or primary amides to isocyanates and (74) (Scheme 26). 

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