A new route to the imidazole-2-thiones from 2-thiohydantoins. Implications in the study of ergothioneine

Abstract

1. 2-Thiohydantoins are reduced by borohydrides to 4(5)-hydroxyimidazolidine-2-thiones, which eliminate water in acid to form imidazole-2-thiones. Both steps take place in mild conditions, in high yield. A number of imidazole-2-thiones have been synthesized by this sequence of steps, with one, two or three substituents in the 1-, 3- and 4(5)-positions. 2. 4(5)-Hydroxyimidazolidine-2-thiones are ammonium pseudo-bases, giving rise to an equilibrium mixture of amino aldehyde, carbinolamine and mesomeric ammonium cationic forms. The elimination of water is suggested to be a property of the mesomeric ammonium cation. 3. The mild conditions in which imidazole-2-thiones are formed from 4(5)-hydroxyimidazolidine-2-thiones are similar to those in which ergothioneine, a naturally occurring imidazole-2-thione of uncertain function, is normally released and measured. It is suggested that the occurrence in vivo of a precursor to ergothioneine, in the form of a 4(5)-hydroxyimidazolidine-2-thione, would explain many otherwise conflicting published data.

Facile Conversion of Amino Acids into 1-Alkyl Imidazole-2-thiones, and Their Oxidative Desulfurization to Imidazoles with Benzoyl Peroxide

“…The classical preparation of 2-thiohydantoins (2THs) is identical in concept to that of I2Ts; acylation of an a-amino ester or acid with a thiocyanate is followed by cyclization of the intermediate. [22][23][24][25][26][27][28] This reaction also traces back at least as far as Marckwald and co-workers. More recently it became famous as the basis of the Edman degradation, wherein the unmasked N-terminus of a peptide is acylated with a thiocyanate; cyclization at the resultant athioureido amide terminus expels a 2TH and a peptide shortened by one amino acid residue.…”

“…3,4,[16][17][18] This entry to an I2T and oxidative desulfurization of it (with nitric acid) dates back at least to Marckwald's 1892 report. 19 Alternative I2T syntheses include condensation of thioureas with a-hydroxycarbonyls, 20 and metal hydride reduction of an a-thioureido ester 21 or a 2-thiohydantoin (2TH) 22 followed by dehydration of the intermediate.…”

Oxidative Desulfurization of Azole‐2‐thiones with Benzoyl Peroxide: Syntheses of Ionic Liquids and Other Azolium Salts

“…1‐Butyl‐3‐methylimidazole‐2‐thione ( 5 ) was isolated in good yield after chromatography. This plan was changed upon finding that 3 completely cyclized to 4 thermally, that 4 was sufficiently electrophilic to undergo sodium borohydride reduction,61 and that crude 4 could be used. We later found the cyclization proceeded more easily with ethanolic potassium hydroxide, and accomplished a water‐insensitive one‐pot synthesis of 5 from 2 .…”

“…The sequence furnishes ILs with varied imidazolium ring substitutents, as seen in the synthesis of [dpim] salts. The sodium borohydride reductions of hydantoins61 with or without their isolation and the one‐pot preparation of 7 are striking, as is the two‐step synthesis of [C 1 mim][OBz] from commercially available sarcosine methyl ester hydrochloride. This protocol also provides a hitherto unknown route to [C n tz] ILs.…”

Biosynthesis of Ergothioneine and Hercynine by Fungi and Actinomycetales

“…Recently, Scott and Henderson (15) suggested that ergothioneine is an artifact of isolation derived from an imidazolidine-2-thione present in the original biological material and formed during isolation (acid conditions). It seems unlikely that this is the case in any of our work because of the very mild conditions of extraction employed.…”