Azides 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/ "" ... 

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. 

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. 

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... 

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. ... 

Dimroth first described, in 1902, the synthesis of l,4 disubstituted 5-amino-l,2,3-triazoles 9, by the reaction of an organic azide, 2/7, with an acetonitrile 8, in the presence of stoichiometric amounts of sodium ethoxide in boiling ethanol, which gave excellent yields for aryl azides 2 (Scheme 4.2) [5]. Long hours of heating were required to carry out the cycloaddition for benzyl azides and even greater difficulties were faced for alkyl azides. 

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