1.2.4- Oxadiazoles substitution

The orientation of the substituent gtoups in 1,2,4-oxadiazole substituted pyrazoles 39, formed by reaction of benzonittile oxides with an unsymmetrically substituted hydrazine, has been determined by C NMR assignments <1998JHC161>. The scope and limitations in the regioselective synthesis of 1,3,5-trisubstituted pyrazoles from / -amino enones and hydrazine derivatives were investigated by C chemical-shift prediction mles for 1,3,5-trisubstituted pyrazoles <2001H(55)331>. 

Other imidazole syntheses include the photoinduced rearrangement of 1,2,4-oxadiazole-substituted enaminones (88JHC1551) and the condensation of 1,2-phenylenediamine-derived enaminones with triethyl orthoformate (89H281). 

Buscemi, S. and Vivona, N., Heterocyclic photorearrangements. Photoinduced rearrangements of 1,2,4-oxadiazoles substituted by an XYZ side chain sequence,/. Heterocyclic Chem., 25,1551,1988. 

Interesting oxadiazole-substituted benzonitriles prepared from the respective aryl iodides were transformed into the corresponding (dioxadiazolephenyl)tetrazoles. Despite the high temperature and other drastic conditions, the oxadiazole ring stayed intact during both reactions (Scheme 20) <1999JOC6425>. 

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. 

Dihydro-l,2,4-oxadiazoles with hydrogen atoms in the 4- and 5-positions are readily oxidized to 1,2,4-oxadiazoles with air or potassium permanganate <87JHClOl>, chlorine <75JOC248l>, or N-bromosuccinimide <86MI 404-02>. This has been used, for example, for the preparation of oxadiazoles substituted with a carbohydrate moiety (Scheme 71) <86MI 404-02). 

No hydrolysis is observed when 2,5-diphenyl-1,3,4-oxadiazole, which has a solubility in water of 0.03%, is treated with mineral acids. Neither concentrated HN03 nor treatment with fuming H2S04 at 100° for 4 hours attacks the oxadiazole ring. Similar stability is shown by 2-(o>-styryl)-5-aryl-l, 3,4-oxadiazole.19 On the other hand, the attempt to obtain the free acid by treatment of 2-phenyl-5-p-car-bethoxyphenyl-1,3,4-oxadiazole with caustic soda produces 1 -p-carboxybenzoyl-2-benzoylhydrazine.23 Other aryl-substituted compounds as well as 1,3,4-oxadiazoles substituted in the 2,5-position by various heterocyclic groups are hydrolyzed by mineral acids.26... 

Scientists from GlaxoSmithKline (GSK) have examined several a-amino- and a-alkoxyphenyl propionic acid derivatives. They have also reported that a-alkoxy phenyl propionic acids are dual PPARa and PPARy agonists, whereas a-amino derivatives are a more selective PPARa agonist. Several oxadiazole-substituted a-isopropoxyphenylpro-pionic acids were evaluated. GSK scientists also made several L-tyrosine-based analogs. The compound selected (farglitazar, 50) was discontinued after phase III clinical trials, due to safety concerns (Scheme 19.15). 

Oxazolines are versatile structures that can undergo chemical transformation into dendrimeric and polymeric systems. Structures (26-28) show cyclotriphosphazenes with phenoxy-oxazoline pendant groups. Both oxazoline and methyl oxazoline groups can be attached to the cyclotriphosphazene ring. Methyl group attachment results in a chiral oxazoline. In a brief report, 1,3,4-oxadiazole substituted cyclotriphosphazene and linear polyphosphosphazene also were synthesized and characterized. ... 

Compounds, 90-95, in Figure 32 are planar compounds that were designed to investigate the effect of the planar geometry on the eventual two-photon properties. The first two compounds along with compound 80 form a series. The number of 2-phenyl-5-(4-tcrt-butylphenyl)-l,3,4-oxadiazole-substituted phenyl rings on the triphenyl amine increases... 

A study of the effect of substitution patterns in oxadiazoles and isoxazoles and their effect on the UV spectra in the lO -lO M concentration range was performed. Hypso-chromic effects and deviations from Beer s law were observed and were believed to be associated with antiparallel, sandwich-type self-association via dipole-dipole interactions. Beer s law is followed when the molecular dipole moments are small or when self-association is sterically hindered. 

Oxadiazole, 2,5-diaryl-electrophilic substitution, 6, 438 as fluorescent whitener, 6, 446 herbicidal activity, 6, 445... 

Oxadiazoles, 6, 365-391 aldol condensation, 6, 383 bond lengths, 6, 378 catalytic hydrogenation, 5, 75 chemotherapy, 6, 391 dipole moments, 6, 378 electron densities, 6, 378 electrophilic substitution, 6, 382 ethers... 

Polyfluoroalkyl- andperfluoroalkyl-substituted CO and CN multiple bonds as dipolarophiles. Dmzo alkanes are well known to react with carbonyl compounds, usually under very mild conditions, to give oxiranes and ketones The reaction has been interpreted as a nucleophilic attack of the diazo alkane on the carbonyl group to yield diazonium betaines or 1,2,3 oxadiazol 2 ines as reaction intermediates, which generally are too unstable to be isolated Aromatic diazo compounds react readily with partially fluorinated and perfluorinated ketones to give l,3,4-oxadiazol-3-ines m high yield At 25 °C and above, the aryloxa-diazolines lose nitrogen to give epoxides [111]... 

Likewise, trifluoromethyl-substituted nitrile imines [172] and nitnle oxides [173,174, 7 75] have been used to synthesize tnfluoromethyl substituted five-membered ring systems of the pyrazole, isomzole, isoxazohne, and 1,2,4-oxadiazole... 

Benzofurazan (benz-1,2,5-oxadiazole) reacted with bromine by addition to give a4,5,6,7-tetrabromo adduct. Bromine in hydrobromic acid solution 4-brominated both 5-methyl- and 5-bromo-benzofurazans (74JHC8I3). When 4,7-dinitrobenzofurazan was treated with ammonium chloride in refluxing acetic acid, nucleophilic displacement gave rise to the 4-chloro-7-nitro derivative (83URP1004375). Naphtho[l, 2-c]furazans (42) are mainly 4-halogenated, but there is minor substitution in the 8-position (73CHE1331). 

There is an extensive literature on the use of 2,1,3-benzoxadiazole 1-oxide [often called benzofuroxanie) (BFO) (462)] as a substrate for the primary synthesis of quinoxaline 1,4-dioxides and occasionally quinoxaline mono-A -oxides or even simple quinoxalines. Very few substituted derivatives of the parent substrate (462) have been employed in recent years. The general mechanism clearly involves a fission (usually amine-catalyzed) of the oxadiazole ring followed by reaction with an ancillary synthon. The following examples are divided according to the type of synthon employed. 

The Ley group also investigated the PS-base/tosyl chloride methodology developed by Brain (see above. Scheme 8) for the synthesis of 2-aminooxadiazoles from semicarbazides, especially with a view to directly synthesize 2-aminosulfonamide substituted 1,3,4-oxadiazoles, a compound class of interest for agrochemical and pharmaceutical apphcations (Scheme 10) [71]. In this case, the choice of the supported base was crucial for the result of the reaction weak bases (PS-DIEA, PS-NMM) could still afford the cyclized 2-aminooxadiazole product, but could not efficiently... 

Finally, a series of 2-chloromethyl-5-aryl-1,3,4-oxadiazoles 82 were prepared by reaction of aromatic hydrazides 81 and a chloromethylorthofor-mate used as the solvent under microwave activation [62]. Potentially, the chloromethyl group could imdergo nucleophiUc substitution expanding the scope of this reaction (Scheme 28). 

Reaction of a perfluoroalkyltetrazole and a perfluoroacyl chloride yields, via a tetra-zolide and under elimination of nitrogen, the corresponding substituted oxadiazole [141]... 

Various derivatives were synthesized from the corresponding nitriles 178 as depicted in Scheme 3. A number of functional groups were introduced, including substituted thiazoles 179, oxadiazoles 180, and pyrimidine 181 <2004JME1329>. 

The concept of five-membered ring heterocyclic synthesis by transformation of the initial adduct of the ADC compound and substrate is not limited to cyclization of substitution products. l,3,4-Oxadiazol-2-ones (30, Scheme 3) result from heating the initial DEAZD-dichlorocarbene adduct.72 Treatment of the Diels Alder adducts 96 with zinc in acetic acid gives pyrroles in good yield (Eq. 17).151 The reaction has been extended to the synthesis of dipyrroles from the appropriate Diels-Alder adduct (96, R = pyrrol-2-yl). 

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