Reactions of 1,3,4-oxadiazoles

Reaction of 1,3,4-oxadiazoles 215 and 216 with either 2-methoxyphenylamine or 2-methoxybenzylamine with heating delivered the corresponding 1,2,4-triazoles 217-219 in low yields (Equation 68 and Table 45)... 

Table 45 Reaction of 1,3,4-oxadiazoles with 2-methoxyarylamines (Equation 68)...

Table 46 Reaction of 1,3,4-oxadiazole-2-(3H)-thiones with hydrazine hydrate (Equation 69)... 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

Reactions of 1,3,4-oxadiazoles at the ring atoms with radicals, carbenes, and nitrenes or with other electron-deficient species are rather uncommon. CHEC(1984) and CHEC-II(1996) have reported very few examples of such reactions concerning oxadiazolinones and oxadiazolinethiones. This situation has not changed. 

The metalation, particularly lithiation, and halogen-to-metal exchange reactions of 1,3,4-oxadiazoles as well as further reactions of organometallic derivatives were reviewed by Grimmett and Iddon (Equation 8) <1995H(41)1525>. 

A [4 + 2]-cycloaddition reaction of 1,3,4-oxadiazole 195 was followed by isomerization and elimination of dinitrogen to provide a pyrrole [160]. 

Nucleophilic attack at substituted ring carbon is probably the most common reaction of 1,3,4-oxadiazoles. However, few examples have been reported of nucleophilic attack at unsubstituted carbon since such compounds (19a) are relatively uncommon. The mechanism of the well-known conversion of 2-amino-oxadiazoles (in aqueous alkali) into triazoles has been studied in the case of the reaction where (19a R = NHPh) is converted to (20). This proceeds via the anion of semi-carbazide PhNHCONHNHCHO and is initiated by hydroxide attack at C-5 <84JCS(P2)537>. A similar nucleophilic attack by hydroxide on oxadiazole (19a R = 5-pyrazolyl) was followed by cyclization to the pyrazolo-triazine (21). Hydrolytic cleavage of 2-ary 1-1,3,4-oxadiazoles to aroyl-hydrazides allows use of the former as protected hydrazides. Oxadiazole (19a R = 4-... 

Reactions of 1,3,4-oxadiazoles at ring atoms with radicals or with electron-deficient species are uncommon. Diazoalkanes R R CN2 reacted with oxadiazolinethiones (22a R = H) to give A -alkyl... 

Tandem intramolecular DA/1.3-DC reactions of 1,3>4-oxadiazoles were reported. The DA reaction step produced the intermediate 231 which was not isolated but evolved, through the loss of nitrogen and a subsequent 1,3-DC, to the final product 232 <02JA11292>... 

Dehydrative cyclization of 3-(5-carboxy)-5-phenyl-4-(pyrrol-l-yI)l,2,4-triazole (508) with poly phosphoric acid gave (82G345) the 1,2,4-triazolo[3,4-/7]l,3,4-thiadiazine (509). Ring transformation of 1,3,4-oxadiazoles to 7//-l,2,4-triazolo[3,4-/>]l,3,4-thiadiazines (507) was reported by Sasaki et al. (82JOC2757) through the reaction of [(1,3,4-oxadiazol-2-yl)thio]ketones (123) with hydrazine hydrate in the presence of acetic acid. 

Wilkie GD, Elliott GI et al (2002) Intramolecular Diels-Alder and tandem intramolecular Diels-Alder/l,3-dipolar cycloadditiou reactions of 1,3,4-oxadiazoles. J Am Chem Soc 124 11292-11294... 

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. 

Microwaves were used to support S-arylation of 5-substituted oxadiazoline-2-thiones <2000BMC69> and <2000M1207>. 5-(4-Pyridyl)oxadiazoline-2-thiones treated with 2-haloesters also afforded A-alkyl derivatives <2000CHE851>. A similar reaction occurred in the case of 5-pyrazolyloxadiazoline-2-thiones <2000JFA5312>. Organophosphorus derivatives of 1,3,4-oxadiazole were obtained by the reaction of bis(oxadiazolinethiones) with 0,0-diethylchlorophosphate (Scheme 21) <1998JFA1609>. 

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). 

This reaction has been widely applied to the synthesis of 1,3.4-oxadiazoles for example, the conversion of 2-acetyltetrazoles 191 leads to the formation of 2,5-dialkyl-l,3,4-oxadiazoles 192 in good yield (Equation 16) <2003EJ0885>. 

The synthesis of 1,3,4-oxadiazoles from tetra-zoles has been reviewed (94ZOB1698). 1,3,4-oxadiazolylacetones 104 (R = H, He, Ph etc) undergo ring-transformation to the isoxazoles 105 by reaction with hydroxylamine (95SYN805). 

Few examples of the alkylation of 1,3,4-oxadiazoles have been reported. The chemical shifts of the 2-methyl protons in the salts formed by protonation or alkylation of 2-methyl-5-phenyl-l,3,4-oxadiazole indicate that reaction takes place at ring nitrogen in position 3 (70JCS(C)1397). Alkylation of oxadiazolines (12) and aminooxadiazole (13) generally results in substitution at ring nitrogen in position 4 or 3 respectively, particularly under neutral conditions. In alkaline media, alkylation at the exocyclic heteroatom may occur. 2-Aryl-A-... 

Thiadiazolidines can be obtained from aliphatic aldehydes or ketones and disubstituted hydrazine derivatives (Scheme 29). A typical preparation of a mesoionic compound consists in the reaction of 1-methylthioacylhydrazine and phosgene (Scheme 31a). Syntheses by three-bond formation are rare for example, a one-pot reaction of an aldehyde with hydrazine and sulfur. A typical ring transformation reaction is the irradiation of 1,3,4-oxadiazoles to yield 1,3,4-thiadiazoles. 

The thermal cleavage of 0(1)-N(1) bond under the action of nucleophiles leading to, in particular, 1,2,3-triazole is the typical reaction of 1,2,4-oxadiazoles, including intramolecular reaction [558],... 

Thus, in an attempt to overcome these disadvantages of classical thermal reactions the microwave technique for the synthesis of 1,3,4-oxadiazoles has rapidly gained acceptance. 

Sangshetti et al. [18] synthesized a novel series of 1,3,4-oxadiazoles (vii) by a one pot reaction of hydrazide (vi), aromatic aldehyde in ethanol water using sodium bisulfate as the catalyst. All the compounds showed good antifungal activities. 

Scheme 93 summarizes the overall reaction much used for the conversion of 1,3,4-oxadiazoles (196 X = O) and thiadiazoles (196 X = S) to triazoles (197) and (198). Intermediates such as (199) and (200) have been isolated in some cases and have been reasonably assumed in others, especially when such amidrazones could be converted either into (197) or (198) according to the reaction conditions (see also 70KGS991). 

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). ... 

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