Oxadiazole derivatives

The herbicide activity ascribed to the 1,2,4-oxadiazole derivative 67 (60) has prompted the search for other biologically active derivatives. This example was prepared from the corresponding 5-chloromethyl-1,2,4-oxadiazole 63 via conversion to the HHT 65 through the aminomethyl analog 64. Reaction of the HHT 65 with diethyl phosphite under neat conditions produced the desired diethyl ester intermediate 66, which was hydrolyzed to 67. 

A new oxadiazole derivative 131 has been prepared in 40% yield by reacting the 1,2-benzoquinone 129 with 1 equiv of A -phenyliminophosphorane 130 product yield rises to almost 80% when 2equiv of phosphorane 130 is used (Equation 24) <2002SC2779>. 

In CHEC(1984) and CHEC-II(1996), only a few papers on crystal studies of 1,3,4-oxadiazole derivatives had been reported. The studies have shown that the oxadiazole and benzene rings in the crystal of 5-phenyl-l,3,4-oxadiazole derivative are nearly coplanar. 

Table 1 Selected bond lengths and angles in 1,3,4-oxadiazole derivatives... 

More recently, some examples of intramolecular Diels-Alder and tandem intramolecular Diels-Alder/l,3-dipolar cycloaddition reactions of especially designed 1,3,4-oxadiazole derivatives have been described (Scheme 3). The... 

In contrast to some 2,3-dihydro-l,3,4-oxadiazole derivatives, for example, compound 4a discussed in Section 5.06.5 and Section 5.06.6.1, the reactions of 2,5-dihydro derivatives 6 or 59 are only described here. 

Oxidative cyclization of acylhydrazones 110a, derived from aldehydes or ketones, with the use of lead tetraacetate (LTA) has been developed into a useful route to several disubstituted and tetrasubstituted oxadiazole derivatives 122, being a convenient source of relatively stable carbenes, like N(0)C , S(0)C , 0(0)C , or S(S)C <2000J(P1)2161 >. Some representative recent examples of the syntheses are collected in Table 2. 

Table 2 Representative examples of the synthesis of oxadiazole derivatives 122 from acylhydrazones 110a...

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

Electroluminescent phenantroline dyes containing triphenylamine and 1,3,4-oxadiazole fragments were prepared using tetrazole-oxadiazole interconversion performed in the presence of aroyl chlorides <2004TL6361>. Also, iV-tributylstannyltetrazoles treated with acetic anhydride gave oxadiazole derivatives <2002RCB357>. 

The photochemistry of 3-amino- <2002JOC6253> and some 3-iV-alkylamino-5-perfluoroalkyl-l,2,4-oxadiazoles <2004JOC4108> was investigated. The latter reaction led to 5-perfluoroalkyl-l,3,4-oxadiazoles followed eventually by their conversion into 5-perfluoroalkyl-l,2,4-triazoles. 1,3,4-Oxadiazoles were also obtained by photochemical interconversion of 3-acylamino-l,2,5-oxadiazole derivatives. Mechanisms of these reactions were proposed <2004JOC4108>. Examples of these interconversions are shown in Scheme 37. 

Dipolar cycloaddition of diazomethane to aldehydes can successfully be used for the preparation of tetrahy-drooxadiazole derivatives. Photochemical interconversion of 3-acylamino-l,2,5-oxadiazole derivatives leads to 1,3,4-oxadiazoles, though the method suffers from lack of selectivity. Many reports concentrate only on the synthesis and applications of new 1,3,4-oxadiazoles substituted with a wide variety of groups without introducing much of new chemistry. 

A number of other derivatives were tested in order to evaluate their biological activity. The spectrum of the activity is very broad. Oxadiazole derivatives were active inhibitors of several enzymes 150 <1996BML2693>, 150a... 

A number of new oxadiazole derivatives exhibited 152a <1998JFA1609>, 152b <1998JME1855>, <2002JFA3757>. 

A series of model nematic liquid crystals (among them oxadiazole derivatives) with transverse dipole moments were used to study the flexoelectric effect in guest-host mixtures with a commercial liquid crystal host <2005CM6354>. 

Dipolar cycloaddition of nitrile oxide at the C=N bond of indole imino esters 130, followed by elimination of the alcohol moity gives oxadiazole derivatives 131 (Scheme 1.26) (298). Reaction of N-arylbenzamidines with arenenitrile N-oxides (generated in situ from oximoyl chlorides) produce unstable 5-amino-4,5-dihydro-1,2,4-oxadiazoles which, on aqueous acidic treatment hydrolyze to open-chain N-benzoyloxy-N -arylareneamidines (299). 

A series of 3,5-diarylisoxazole and 3,5-diaryl-l,2,4-oxadiazole derivatives, novel classes of small molecule interleukin-8 (IL-8) receptor antagonists, 456 (Ar = 4-FC6H4), have been identified as IL-8 inhibitors. These compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of IL-8 induced... 

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

The reaction of 5-aryl-3-(chloromethyl)[l,3,4]oxadiazole-2(3//)-thiones 100 with hydrazine or methylhydrazine yields the corresponding 2,3-dihydro[l,2,4]triazolo[3,4-A][l,3,4]oxadiazole derivatives 102 <1984JCED477>. By analogy, hydrazine and phenylhydrazine convert the [l,2,4]triazole-2(3//)-thiones 101 into 3,7-dihydro-2//-[l,2,4 tria-zolo[4,3-r][ 1,2,4] triazoles 103 <1992PS99, 2002JCCS1035>. Finally, the azole-2(3//)-thiones 101 react with hydroxylamine to form the 3,7-dihydro[l,2,4]triazolo[5,l-d[l,2,4]oxadiazoles 104 (Scheme 8) <1992PS99>. 

J.J. Kim, K.-S. Kim, H.C. Kim, and M. Ree, Synthesis and properties of photoluminescent polymers bearing electron-facilitating oxadiazole derivative side groups, J. Polym. ScL, Part A Polym. Chem., 40 1173-1183, 2002. 

M. Berggren, G. Gustafsson, O. Inganas, M.R. Andersson, T. Hjertberg, and O. Wennerstrom, White light from an electroluminescent diode made from poly[3(4-octylphenyl)- 2,2 -bithiophene] and an oxadiazole derivative, Appl. Phys. Lett., 76 7530-7534, 1994. 

Heterocyclic ring systems are also used to connect two anthraquinone groups. Typical examples include Cl Vat Red 10 (6.106), which is an oxazole derivative obtained from 2-amino-3-hydroxyanthraquinone and the appropriate acyl chloride, the similar thiazole derivative Cl Vat Blue 31 (6.107) and the oxadiazole derivative Cl Vat Blue 64 (6.108). 

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