Diacylhydrazines 1.3.4- oxadiazoles

In the preparation of novel 1,3,4-oxadiazoles 56 from 1,2-diacylhydrazines 55, Brain and coworkers [29] used a highly efficient cydodehydration assisted by use of micro-waves, in THF as solvent, using polymer-supported Burgess reagent (Scheme 8.21). 

The dehydration of A,A -diacylhydrazines is a standard method for the formation of the 1,3,4-oxadiazole ring. 2,5-Dipicryl-l,3,4-oxadiazole (DPO) (19) is synthesized by treating 2,4,6-trinitrobenzoic acid (17) with phosphorous pentachloride, followed by treatment with hydrazine to give the A, A -diacylhydrazine (18) which undergoes dehydration on further reaction with phosphorous pentachloride in 1,2-dichloroethane. DPO exhibits high thermal stability but is very sensitive to impact and shock, making it useful in detonation transfer compositions. 

The malonate derivative (93) reacted with acylhydrazine (94) to give a mixture of diacylhydrazine monoenamine (95) and oxadiazole (88c), (Scheme 6) which was also formed from (95) on heating <88LA909). 

No important new general routes to 1,3,4-oxadiazoles have been reported since the mid-1980s. The major routes (as emphasized in both CHEC-I, and in the preceding two sections, 4.06.9.1 and 4.06.9.2) are (i) the formation of oxadiazoles by cyclodehydration of diacylhydrazines... 

An analogous meso-ionic l,3,4-oxadiazol-2-ene (168) in which the negative charge is associated with a fluorenyl residue has also been recently described. The A, iV -diacylhydrazine (166) and acetic... 

Oxadiazoles have often attracted the attention of medicinal chemists as stable bioiso-steres of metabolically labile esters. 1,3,4-Oxadiazoles are generally prepared by cyclodehydration of 1,2-diacylhydrazines or their equivalents. Symmetrical 2,5-disubstituted examples were able to be rapidly prepared in a one-pot condensation-cyclodehydration of benzoic acids (2 equiv) with hydrazine dihydrochloride, in the presence of... 

Brain, C.T., Paul, J.M., Loong, Y. and Oakley, P.J., Novel procedure for the synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using polymer-supported Burgess reagent under microwave conditions, Tetrahedron Lett., 1999, 40, 3275. 

Sydnones 78 (R1 = Ph, Ar or 3-pyridyl, R3 = H or Me) are obtained from the nitrosoamino acids 77 and acetic anhydride under ultrasound (94MI153). Three examples of the formation of oxadiazoles by microwave irradiation are from O-acyl amide oximes 79 in the presence of aluminium oxide, from amide oximes 80 and isoprop-enyl acetate in the presence of KSF-clay and from N,N -diacylhydrazines 81 and thionyl chloride (95SC1451). 

In a subsequent study, the impact of replacing one or both of the amide bonds with either a diacylhydrazine or a 1,3,4-oxadiazole was explored [36]. (fi)-Bromoallyl ethers were employed in the PI and Pi positions and similarly subjected to Suzuki conditions using the two aryl boronic acids that gave the most potent inhibitors in the previous study. Potent plasmepsin inhibitors were produced however, no real improvements in activity compared to the parent compound were observed (Scheme 5). The use of the preligand, [(f-Bu3)PH]BF4 [37], in combination with barium hydroxide was found beneficial although the yields were very low in these reactions. 

Alkyl- and aryl-1,3,4-oxadiazoles (20) undergo acid- or base-catalyzed ring opening in water. Susceptibility to hydrolysis increases with solubility (Section 4.23.2.3). Hence alky-loxadiazoles ring-open more readily than aryloxadiazoles and 2,5-diaryl-l,3,4-oxadiazoles are fairly stable in dilute acid or alkali at 100 °C. The initial product of hydrolysis is a diacylhydrazine (21) which suffers further hydrolysis under more vigorous conditions. 

The most widely applicable route to 2,5-dialkyl-, 2-alkyl-5-aryl and 2,5-diaryl-l,3,4-oxadiazoles (76) is the thermal or acid catalyzed cyclization of 1,2-diacylhydrazines (75 Scheme 13). The method may also be used for monosubstituted oxadiazoles (76 R1 = H) and esters (76 R2 = CQ2R) (78GEP2808842). 

Substituted acylhydrazones (95), formally derivatives of 1,2-diacylhydrazines (75), also cyclize to oxadiazoles (76), with loss of HX. Imidol ethers (95a R2 = H), prepared from acylhydrazines R1CONHNH2 and ortho esters HC(OR)3, cyclize on heating to monosub-stituted oxadiazoles (76 R1 = H). This reaction is an important synthesis of monosubstituted... 

A single pot synthetic protocol for the synthesis of 2-sulphonamide-l,3,4-oxadiazoles from 1,2-diacylhydrazine (xxix) under microwave irradiation using PS-BEMP (xxxi) and corresponding sulfonyl chloride (xxx) is reported by Baxendale et al. [33]. 

Computational studies concerning theoretical approaches to the intrinsic basicity of neutral nitrogen bases have been reported, including those of phos-phoranimines. The non-ionic phosphazene bases BEMP (112), BTPP (113) and (114, R = Ph) appear to be excellent catalysts for the Michael addition reactions. Thus the yield of the coupling reaction of ethyl isocyanoacetate with l,2-bis(4-bromomethylphenyl)ethane is increased by the addition of the phosphazene base BEMP. Polymer-supported BEMP (P-BEMP) has been applied for the allylation of 2H-benzo[d]l,3-dioxolan-5-ol by allyl bromide. " Cyclodehydration of 1,2 diacylhydrazines by tosyl chloride in the presence of P-BEMP leads to excellent yields of 1,3,4,-oxadiazoles. Addition of P-BEMP also improves the yield of the Hofmann elimination step in the synthesis of tertiary mines using REM resin (polymer-bound acrylate ester). ... 

Under anhydrous conditions 3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine isomerizes to the 4-amino-1,2,4-triazole derivative (326). Hydrolysis under the influence of acids or bases transforms the 1,4-dihydro-1,2,4,5-tetrazine system to diacylhydrazines (329), carboxylic acids (330), and hydrazine, 1,3,4-oxadiazoles (328), or 1,2,4-triazoles (327) depending on the reaction conditions <78HC(33)1077>. 

CycUzations and cycloadditions. Treatment of Al,Al -diacylhydrazines and y,8-unsaturated ketone O-pentafluorobenzoyloximes with (PhiP)4Pd generates 1,3,4-oxadiazoles and substituted pyrroles, respectively. 

Oxadiazoles are available by cyclodehydration of A.A -diacylhydrazines or their equivalents. They are also available from tetrazoles (section 26.1.1.3) or by oxidative cyclisation of acyl hydrazones. ... 

Thiadiazoles are available by a number of convenient general routes including cyclisation of A, A -diacylhydrazines, or 1,3,4-oxadiazoles, with phosphorus sulfides. 3-Amino-1,3,4-thiadiazoles are prepared via acylation of thiosemicarba-zides and the parent compound is easily obtained from hydrogen sulfide and dimethylformamide azine. ... 

Oxadiazoles 165 result when W.W-diacylhydrazines are treated with the triphenylphosphiiie-carbon tetrachloride adduct in the presence of triethylamine <97PJC77>. Acylhydrazines 166 (R = Me, i-Pr, n-Bti, Ph or Bn) react with ketenylidenetriphenyl-phosphine 167 in boiling xylene to yield the 1,3,4-oxadiazoles 168 (Scheme 9) <97SL283>. 

Oxadiazoles are prepared in good yields from silylated diacylhydrazines (formed in situ) by acid-catalyzed cyclization using TfOH (eq 14). ... 

Oxadiazoles are available by cyclodehydration of A,A -diacylhydrazines or their equivalents. ... 

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