1.3.4- Oxadiazoles, mesoionic

The mesoionic tetrazole dehydrodithizone is transformed by iron penta-carbonyl into 4-phenyl-2-phenylazo-A2-l,3,4-thiadiazolin-5-one, presumably by a mechanism of ring opening, complexation, carbonyl insertion and subsequent ring closure (Scheme 128).193 Unfortunately, analogous processes do not occur on other mesoionic compounds in the 1,2,3-oxadiazole, s-triazole or tetrazole series, and the scope of this unusual carbonylation is probably limited. 

The reactions of substituents on ring nitrogen atoms in 1,3,4-oxadiazolium cations 2 and exocyclically conjugated mesoionic 1,3,4-oxadiazoles 3 are uncommon. Similar reactions of compounds 4 and 5 were reported occasionally. Biphenylmethylation of 2-trifluoroacetamido-l,3-4-oxadiazole 105 occurred regioselectively (Scheme 23), affording only the 2-acylimino derivative instead of the expected product 106 <1997H(44)133>. 

Mesoionic derivatives are generally synthesized from the parent 1,2,3-thiadiazoles. A new method based on the rearrangement of oxadiazoles under reductive conditions has been reported. For example, the oxadiazole 70 when... 

A mesoionic compound PR-G-138-C1 (XXXIX) from Pharma Research in Canada is reported to lower blood pressure in man at low doses by a vasodilator type mechanism (43). This structure is related to SIN-10 (XL) which was reported earlier by Japanese scientists as active in dogs (44). Compounds related to structure XXXIX were compared in spontaneous hypertensive rats and those with the oxadiazole ring hydrogen replaced by chlorine or bromine were as active as the parent compound, although replacement by methyl caused a loss of activity (45). 

Mesoionic oxadiazoles are available from 2(l//)-pyridones and methyl isocyanate via carbodiimide (88CB1495). 

The chemistry of the 1,2,3-oxadiazole ring system is confined almost entirely to the mesoionic sydnones and related compounds. Sydnones are sensitive to hydrolysis, especially in basic media where they are rapidly cleaved. Nevertheless a range of useful reactions of sydnones, involving both ring cleavage and substitution with retention of the ring system, is known. Many of the publications that have appeared in the period 1982-1995 represent modifications or extensions to known reactions of sydnones. The subjects covered include the following. 

Thiadiazoles and 1,3,4-oxadiazoles are closely related in their reactivity, and can also be prepared from common precursors. They also undergo ring transformations and the thiadiazoles can be obtained directly from the oxadiazoles. 2-Thio-5-(4-pyridyl)-l,3,4-oxadiazole (157) (Equation (23)) when heated under reflux in ethanolic HCl rearranges to the 2-hydroxythiadiazole derivative (158). The mesoionic oxadiazole (159) also rearranges to the thiadiazole (160) when heated in ethanol (Equation (24)) <84CHEC-I(4)545>. 

Huisgen, Gotthardt, and Grashey518 have shown that 4,5-diphenyl-isosydnone (99) reacts with EPP in p-cymene at 150° giving the corresponding pyrazole ester (103) in 53% yield. Ohtaand Kato have stated 519 that these mesoionic-l,3,4-oxadiazoles do not react with dialkyl acetylenedicarboxylates either thermally or photochemically. McCarthy,... 

Unlike the mesoionic 1,2,3-oxadiazoles (see Chapter 5.03), mesoionic 1,2,3,4-oxatriazoles 5 and 6 do not undergo 1,3-dipolar cycloaddition reactions. Azides formed by loss of carbon dioxide from anhydro-5-hydroxy-l,2,3,4-oxatria-zolium hydroxides 4, on prolonged heating with lithium chloride, may be trapped by cycloaddition to an alkyne < 1996CHEC-II(4)679>. 

Oxadiazole (1) is a thermally stable neutral aromatic molecule (65JA5800). Other aromatic systems are 1,3,4-oxadiazolium cations (2) and the exocyclic-conjugated mesoionic 1,3,4-oxadiazoles (3) and 1,3,4-oxadiazolines (4). Also known are derivatives of the non-aromatic reduced systems, 2,3-dihydro-l,3,4-oxadiazole (A2-l,3,4-oxadiazoline 5),... 

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. 

Previously only a few condensed 1,3,4-oxadiazoles were known. Pyrido[2,l-6]l,3,4-oxadiazol-2-one and the quinoline analog are obtained by the action of phosgene on l-aimnopyrid-2-one and 1-aminoquinol-2-one, respectively.118 These compounds display a mesoionic character. Furthermore, imidazolo[2,1 -6] 1,3,4-oxadiazoles... 

Conversions of 2-amino-5-carboxy-l,3,4-oxadiazole (211) and of the mesoionic acyl-aminooxadiazole (212) (73KGS1345) into the triazolinones (213) and (214) are normal (Scheme 97). The latter reaction occurs with deacylation, of course. 

CN and /cn couplings for some mesoionic oxadiazoles and thiadia-zoles have been determined by Jaiwihski et All /ch and Jcc couplings have been determined by Bednarek et for 5-halogenouracils and used for assigning the carbon signals. Jcc couplings have been measured by Sommer et al for some di- and trisubstituted pyrazines and by Cmoch et for A(l)-oxide and A(3)-oxide forms of pyridofuroxan[l,2,5]oxodiazolo[3,4-Z ]pyridine oxide. 

Oxadiazoles," 1,3,4-oxadiazoles" and 1,2,5-oxadiazoles are well known, but the 1,2,3-oxadiazole system, which calculations indicate to be unstable relative to its ring-open diazo-ketone tautomer," is known only as a benzo-fused derivative (in solution) and in mesoionic substances, known as sydnones ," which have been well investigated. Furoxans ," which are formed by the dimerisation of nitrile oxides, have also been extensively studied. 1,2,3-Thiadiazoles, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles" and... 

Perhaps the most studied of oxadiazoles are the sydnones and some views on their aromatic character are summarized here. For detailed reviews the reader is referred to Ohta and Kato,244 Bloor et al.Ub Stewart,246 and Baker and Ollis.247 The sydnones may be represented by structures 57a-d, of which the mesoionic structure 57a most clearly implies an aromatic sextet. 

The reaction of 3-benzoyl-l,2,4-oxadiazoles 271 with hydrazine affords 1,2,4-triazines 272 <2005JOC3288> (Scheme 161), while, on treatment of mesoionic trifluoroacetyl-l,3-oxazolyl-3-olate 273 with phenylhydrazine,... 

Sydnones (1) are mesoionic, that is, betaine-hke compounds (analogous to Miinchnones, cf. p. 175) structurally derived from the 1,2,3-oxadiazole system ... 

With the exception of mesoionic compounds such as sydnone 1 (Fig. 1) [2], fluorinated 1,2,3-oxadiazole systems are rare and often included as structures in patent s Markush, without sufficient experimental details [3]. 

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