Triazoles Dimroth synthesis

In the case of some fused [l,2,4]triazoles, Dimroth rearrangements to the appropriate isomeric ring systems have been observed. Thus formations of (16) from (15) <84JCS(Pl)993>, (20) from (21) <90JCS(P2)1943>, and (32) from (30) <82JHC1345> have been reported. These transformations are also discussed in the respective sections on synthesis. 

The 1,3-dipolar cycloaddition of azido-l,2,5-oxadiazoles (azidofurazans) to dicarbonyl compounds has been studied and a new procedure for the synthesis of (l,2,3-triazol-l-yl)-l,2,5-oxadiazoles was proposed <2002MC159>. The cycloaddition of 4-amino-3-azido-l,2,5-oxadiazole 168 to nitriles with activated methylene groups has been studied, and 3-amino-4-(5-amino-l/7-l,2,3-triazol-l-yl)-l,2,5-oxadiazoles 169 and the products of their Dimroth rearrangement 170 have been synthesized <2004MC76>. 

Examples of the Dimroth rearrangement (Section IV, F) include several s3mtheses of monocyclic triazoles from other heterocyclic systems (cf. Scheme 25). Triazole-5-thiols can be prepared by treatment of 5-amino-l,2,3-thiadiazoles with bases.A similar base-induced rearrangement of sydnoneimines provides a synthesis of 4-hydroxy-triazoles. ... 

Synthesis of this ring may be achieved by the construction of one of the heterocycles followed by using it as a basis to build the other ring onto it or by the Dimroth rearrangement of l,2,4-triazolo[4,3-a]pyrimidines. 1,2-Diaminopyrimidines are general precursors, and they can be generated from 1-amino or 2-aminopyrimidines. The 3- and 5-amino-l,2,4-triazoles are alternative precursors that can act as a source of three carbons to complete the pyrimidine ring. 

L abbe and his collaborators have also demonstrated the importance of electronic effects in the synthesis of 1-vinyl-1,2,3-triazoles by adding azides ta either acetylenes (Eq. 15) or active methylene compounds (Eq. 16). In both cases iodoalkyl azides may be added, with comparable results, to produce precursors of 2.2-4 and 2.2-5. This very productive group has pioneered the excellent general method for l,5-disub tituted-l,2,3-triazoles involving phosphorus ylides (Eq. 17). The high yields and wide range of substituents employed makes this method most attractive. Product structures were demonstrated by the Dimroth addition and decarboxylation (Eq. 16). 

Perhaps the most intensively studied synthesis of amino-1,2,3-triazoles is the base-catalyzed condensation of nitriles with azides and the following rearrangement discovered by Dimroth (Eq. 14). Lieber and Rao have made detailed studies of the relationship of cyclization to rearrangement and have shown the optimum conditions for the isolation of 6.1-7 and 6.1-S. ... 

The second new synthesis of 7-methoxymitosene (3) was published by Wender and Cooper [34]. Based on a novel triazole photolysis, it affords the product in 8.3% yield after 12 steps. It is more efficient than the original synthesis of 3, but it requires more steps than the synthesis reported by Luly and Rapoport in 1984. As illustrated in Scheme 12, it began with 2,6-dimethoxytol-uene (91), which was converted into azido derivative 92 by the sequence of nitration, catalytic reduction, diazotization, and treatment with sodium azide. Dimroth condensation of 92 with ethyl 6-triisopropylsiloxy-3-oxohexanoate in... 

The venerable Dimroth triazole synthesis is a base-catalyzed condensation of an azide 1 with an active methylene compound 2 to provide a 1,2,3-triazole derivative 3. Commonly, this reaction is run with an alkoxide base in the corresponding alcohol solvent at ambient temperature or reflux/ "" ... 

Otto Dimroth was a professor at the University of Tubingen in Germany when he reported the Dimroth triazole synthesis in 1902, and subsequently the Dimroth rearrangement in 1909 (see Section 9.4). His name is commonplace in chemistry labs throughout the world for the water condenser that bears his name. 

State-of-the-art condensation chemistry has changed little since the turn of the 20th century when Dimroth first reported his novel method for 1,2,3-triazole synthesis. Still, replacement of the alkoxide base and alcohol solvent with several alternatives has extended the scope of the original reaction and has made possible a variety of interesting tandem processes vide infra). 

Cottrell et al. at Merck Sharp and Dohme Research Laboratories reported a mild procedure that used potassium carbonate in dimethyl sulfoxide. These conditions were compatible with highly functionalized benzyl azides, and extended the substrate scope of active methylene compounds to acetoacetone and benzoylacetone. This extension provided access to acyl-1,2,3-triazoles 21 for the first time via the Dimroth triazole synthesis. 

As reported in 1902, the substrate scope of the Dimroth triazole synthesis was limited to aromatic azides. An early extension of this methodology was reported in 1956 by Hoover and Day at the University of Pennsylvania. IH-1,2,3-Triazoles were of particular interest at the time as potential modifiers of nucleic acid metabolism. As part of a program directed at cancer chemotherapies, they replaced the azide aromatic moiety with a benzyl substituent. Sodium ethoxide-promoted reaction of benzyl azide (19) with active methylene compounds 25 provided 1-benzyl-1,2,3-triazoles 26 that could undergo reductive cleavage with sodium in liquid ammonia to afford the desired 4,5-disubstituted species. While various active methylene compounds were successfully used (ethyl cyanoacetate, cyanoacetamide, cyanoacetic acid, and malononitrile), the yields were low to modest when compared with aromatic substrates. ... 

While at the University of Colorado, L Abbe and Hassner extended the scope of the Dimroth triazole synthesis to vinyl azides. These substrates could be obtained through technology developed in their lab provided W-vinyl triazoles for the first time. " This report also described p-haloalkyl azides as suitable iV-vinyl triazole precursors following an elimination event. It is unclear whether elimination occurs before or after triazole formation. 

A recent report from the Ukrainian group of Obushak et al. takes advantage of the conventional Dimroth triazole synthesis conditions to... 

In a closely related report, Obushak et al. extended the active methylene seope to another example of a 6,5-fused bicycle. Onee again, traditional Dimroth triazole synthesis conditions gave the desired triazole 37 from lH-benzimidazol-2-ylacetonitrile 36 and aryl azides en route to [ 1,2,3]triazolo-[4, 5 4,5]pyrimido[ 1,6-a]benzimidazole 38. 

A third report from Obushak, Pokhodylo, and Matiychuk used (arylsulfonyl)aeetones 40 and (arylsulfonyl)acetonitriles as activated methylenic building bloeks for 1,2,3-triazoles 41. Conventional Dimroth triazole synthesis conditions provided 4-arylsulfonyl triazoles in moderate to good yield with mild or no heating when aryl azides were used. 

Utility of the Dimroth Triazole Synthesis in Tandem Reaction Sequences... 

The first observed tandem process accompanied the discovery of the Dimroth triazole synthesis. Otto Dimroth reported on the propensity of his newly formed triazole product to undergo a rearrangement in which a cyclic C-N bond was broken, followed by a C-N bond forming event in which the endocyclic and exocyclic nitrogens had reversed (See Section 9.4) ... 

While pursuing a program directed at new ligands for GABAa receptors, Jones and Chambers developed a rapid approach to C-5 substituted l,2,3-triazolo-[l,5-a]quinazolines. Reaction of 2-azidobenzoic acid (46) with an isoxazole acetonitrile 47 under classical Dimroth triazole synthesis conditions gave the desired core skeleton with a chemical handle for rapid derivitization. 

Dimroth Triazole Synthesis Methyl 5-amino-l-(4-iiitrophenyl)-liy-l,23-triazoIe-4-carboxylate (18) ... 

Hesse and Ognyanov employed the Dimroth rearrangement in their synthesis of 5-(phenylamino)-l//-1,2,3-triazole 196/ This molecule was obtained in nearly quantitative yield by refluxing the corresponding 5-amino-1-phenyl-1//-1,2,3-triazole 195 in pyridine for 6 h. 

Batog and co-workers used the Dimroth rearrangement to prepare a series of novel monosubstituted AT-(4-substituted-l//-l,2,3-triazol-5-yl)-1,2,5-oxadiazole-3,4-diamines (furazans). Substituted-5-amino-l, 2,3-triazole derivatives have previously been shown to display a variety of pharmacological activities, and the synthesis of furazans was undertaken in an effort to compare their reactivity and biological activity to known substituted-5-amino-1,2,3-triazole derivatives. 5-Amino-1,2,3-triazole derivatives 197, 199, 201 and 203 rearranged to form the mono-substituted diaminofurazans 198, 200, 202 and 204 upon continuous heating at 85-95 °C in DMF for 1 h, with yields of between 52 and 87%. 

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