1.2.4- Triazolines aromatization

The products are triazolines with the amino or alkoxy function in the 5-position Addition is regiospecific. In some cases the triazolines aromatize spontaneously more usually, aromatization is effected by heating the compounds alone (for enol ether adducts) or with acid or base. 

Triazoline aromatization to triazoles can be achieved by oxidation, isomerization reactions, and elimination of stable molecular fragments, all of which require the presence of a free hydrogen at position 4 and/or 5 of the triazoline ring. The aromatization reaction affords a selective, synthetic route for the preparation of triazoles of definitive structure, inasmuch as azide addition to acetylenes is not regioselective.33... 

The reaction of l-morpholylbut-l-en-3-yne with aromatic azides gives 1-aryl-4-ethynyl-5-iV-morpholino-A -triazolines (164), which readily eliminate morpholine to form l-aryl-4-ethynyltriazole (165) during chromatographic purification (83DIS). 

A different result was obtained in the cycloaddition to methylenecyclo-propanes 216-218 tearing alkoxycarbonyl substituents on the cyclopropyl ring. In this instance, 1,2,3-triazoles 220 isomeric with the triazolines 219 were formed in the reaction [57]. The formation of triazoles 220 is rationalised by the intermediate formation of triazolines 219, which are unstable under the reaction conditions and undergo a rearrangement to the aromatic triazoles via a hydrogen transfer that probably occurs with the assistance of the proximal ester carbonyl (Scheme 35). The formation of triazoles 220 also confirms the regio-chemistry of the cycloaddition for the methylene unsubstituted methylene-cyclopropanes, still leaving some doubt for the substituted ones 156 and 157. 

Photolysis of the azirines 68 in the presence of DEAZD gives 1,2,4-triazolines (69, R = Et) via cycloaddition to the nitrile ylid.114 The nitrile ylid generated thermally from 70 gives 1,2,4-triazolines (69, R = Me, R1 = R2 = CF3) (Scheme 7).11S The cycloadditions proceed in good yield, and the triazolines 69 are readily converted into aromatic 1,2,4-triazoles. 

Triazolines have been aromatized in good yield under two-phase conditions using potassium permanganate in the presence of tetra-n-butylammonium chloride [49]. 

Imines derived from ketones with an a-methylene group can react via their enamine tautomers, and mixtures of triazoles are also isolated from these systems. The triazoline adducts of the enamine tautomers are aromatized by treating with acid, and in these conditions the triazoline appears to undergo a Dimroth rearrangement before elimination of the amine, because two triazoles are obtained, one of which has... 

The energy gained in producing the aromatic triazole system facilitates the retro-Diels-Alder reaction of suitably substituted triazolines. The reaction is potentially useful as a method of synthesis of highly reactive species (e.g.. Scheme 18) rather than as a preparative procedure for triazoles. 

Further disadvantage of the alkyne-azide cycloaddition is the lack of regiospecificity. On the other hand, cycloadditions of azides to alkenes are, in most cases, regioselective and afford 1,5-disubstituted triazolines . Therefore, the regioselective cycloaddition of an azide to an alkene, followed by aromatization (see Section 4.01.5.3.1) is an alternative method for the synthesis of 1,2,3-triazoles. 

Only those compounds which do not have tautomeric aromatic triazole structures will be considered here, the others having been treated as triazoles. The triazolines are unstable and have been subjected to little study. Compounds which are disubstituted at the C(3) or C(5) atom are more stable than the mono- or unsubstituted analogues. The equilibrium has been observed by NMR spectroscopy between the six-membered tetrazine (75) and the triazolinethione (76) via the open-chain form, thus mirroring monosaccharide equilibria (Scheme 12) <90TL3927>. 

Again, as with the triazolines, only those compounds which do not have tautomeric aromatic triazole structures would be treated here and these systems are unstable and have been even less studied than their dihydrocounterparts. 4-Phenyltriazolidininedione is a precursor of PTAD (see Section 4.02.6.3). 

Phenylthiosemicarbazones (198) of aromatic aldehydes and ketones give 1,2,4-dithiazolidines (199) with the same reagent, whereas those of aliphatic ketones produce 1,2,4-triazolines only (Equation (20)) <91JHC1957>. Aromatic and heteroaromatic thiodihydrazones (200) in the same reaction conditions afford 1,2,4-dithiazolidines (201) (Equation (21)) <91JHC1957>. 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

Soufiaoui and co-workers (19) reported an intermolecular 1,3-dipolar cycloaddition of tosyl azide with the 1,2-dihydroisoquinoline 81 to give the triazoline 82, which, on extrusion of nitrogen followed by aromatization via elimination of H2 or... 

Where the carbon-carbon double bond is a part of an aromatic system, in general, cyclopropanation of diazoketones results in the formation of unstable cyclopropane adducts. For example, Saba140 has shown that in the intramolecular cyclopropanation of diazoketone 57 the norcaradiene ketone 58 can be detected by low-temperature NMR and can be trapped in a Diels Alder reaction with 4-phenyl-l,2,4-triazoline-3,5-dione (equation 69). In addition, Wenkert and Liu have isolated the stable norcaradiene 60 from the rhodium catalysed decomposition of diazoketone 59 (equation 70)105. Cyclopropyl ketones derived from intramolecular cyclopropanation of hetereoaromatic diazoketones are also known and two representative examples are shown in equations 71 and 72106. Rhodium(II) compounds are the most suitable catalysts for the cyclopropanation of aromatic diazoketones. 

The (azidofuranosyl)uracil (212) cyclized at 110 C to afford a mixture of mostly a tricyclic triazole and lesser amounts of a tricyclic pyrimidine.117 A triazoline intermediate was hypothesized indeed, the triazoline could be intercepted by DDQ-effected aromatization to afford the corresponding tetracyclic triazole. Evidence was presented that the major product was in equilibrium with the triazoline at the reaction temperature. 

The addition of aromatic sulfonyl azides to simple acyclic and cyclic dienes in a 1 2 molar ratio has been investigated.184 In no case was the triazoline... 

In a search for cytostatic quinones, both benzoquinones and naphthoquinones have been treated with glycosyl azides labile N-glycosyl triazolines are formed, which aromatize to triazoles or lose nitrogen to give enamines.317... 

Hydroxy triazolines, isolable or formed in transit (Scheme 64)2SS,26i-263 undergo aromatization by dehydration. l-Alkyi-5-hydroxytriazolines can be dehydrated by the action of trifluoroacetic acid256,262 however, the 1-aryl counterpart loses nitrogen to give various rearrangement products.262... 

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