Synthesis of 2-Hydroxymethyl-1H-imidazoles from 1,3-Dihydroimidazole-2-thiones

Abstract

S y n t h e s i s o f 2 -H y d r o x y m e t h y l -1 H -i m i d a z o l e s f r o m 1 , 3 -D i h y d r o i m i d a z o l e -2 -t h i o n e sAbstract: 1,3-Dihydroimidazole-2-thiones 1a-d were desulfurized by hydrogen peroxide in either acid or neutral medium to afford 1H-imidazoles 3a-d. Reaction of 3b,d with dimethylsulfamoyl chloride furnished N,N-dimethylsulfamoylimidazoles 5 and 6a,b. Lithiation of 5 and 6a,b followed by formylation and reduction yielded the 2-hydroxymethyl derivatives 7 and 8a,b. 4-Alkyl-5-cyclohexylmethyl-1H-imidazol-2-yl)methanols 9a,b were obtained by hydrolysis of 7 and 8a,b.Desulfurization of sulfur-containing compounds, including thioureas, has been achieved by using a number of different reagents. Raney nickel has being the most often employed; 1 other methods involved the use of nickel-sodium hydride complexes 2 and transition metal compounds, 3 alkali bromates and iodates, 4 nitric acid, 5 potassium superoxide, 6 oxygen and potassium tert-butoxide, 7 ozone, 8 3,3-dimethyldioxirine, 9 and a photochemical reaction involving singlet oxygen. 10,11 Alkaline hydrogen peroxide has been used for the oxidation of pyrimidine-2-thiones to the corresponding sulfinic acids. Subsequent refluxing of the isolated sulfinic acids with sulfuric acid afforded the desulfinated pyrimidines. 12 Alkaline hydrogen peroxide and sodium peroxide have also been used for the conversion of thioureas into ureas. 13 In this work, hydrogen peroxide was used for the desulfurization reaction of 1,3-dihydroimidazole-2-thiones in acid and neutral medium followed by hydroxymethylation at the 2-position. 2-(Hydroxymethyl)imidazoles are interesting starting materials and have been used in a practical synthesis of immunosuppressant compounds. 14 4-Benzyl-5-ethyl-1,3-dihydroimidazole-2-thione (1a) has been previously synthesized by Bullerwell and Lawson, 15 4-benzyl-5-isopropyl-1,3-dihydroimidazole-2-thione (1c) 16 and 5-alkyl-4-cyclohexyl-1,3-dihydroimidazole-2-thiones 1b,d 17 have been synthesized by Loksha et al. 16,17 In the present investigation we found that treatment of 1,3-dihydroimidazole-2-thiones 1a-d with hydrogen peroxide in an acidic medium afforded 1H-imidazole-2-sulfinic acids 2a-d as the major products and the desulfurized imidazoles 3a-d as the minor products. Treating compounds 1a-d with hydrogen peroxide in a neutral medium in ethanol furnished the desulfurized imidazoles 3a-d as the major products and the ethyl esters of 1H-imidazole-2-sulfinic acids 4a-d as the minor products. The imidazole-2-sulfinic acids 2a-d are somewhat stable in acidic medium and only small amounts were converted to the desulfinated imidazoles 3a-d through elimination of sulfur dioxide which is further oxidized to sulfuric acid by an excess of hydrogen peroxide. Under neutral reaction conditions in ethanol, small amounts of the initially formed sulfinic acids were esterified by the solvent to compounds 4a-d, whereas the major part of the sulfinic acids were converted to compounds 3a-d (Scheme 1). 5-Benzyl-4-ethyl-1H-imidazole (3a...