DIMROTH Triazole Synthesis

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. 

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) ... 

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