A New Class of Fused Imidazoles by Intramolecular Nucleophilic ipso-Substitution in 2-Alkylsulfonylimidazoles: Synthesis of 2,3-Dihydroimidazo[2,1-b][1,3]oxazoles

Abstract

Starting from readily available thiouronium salts 1 and ahalocarbonyl compounds 2, a simple and efficient synthesis of 2-alkylthioimidazoles 3 was accomplished. Reduction of the carbonyl group, followed by oxidation of the 2-alkylthioether moiety, afforded sulfones 8. Intramolecular nucleophilic ipso-substitution in 2-alkylsulfonylimidazoles 8 efficiently furnished a novel class of fused imidazoxazoles. This finding was extended towards the generation in solution of a small library of 2,3-dihydroimidazo[2,1-b] [1,3]oxazoles.Heteroaromatic nucleophilic addition-elimination reactions are commonly recognized in many electron-deficient heterocycles. 2 However, analogous reactions with electron-rich heterocycles, 3-5 and more accurately, with electron-rich imidazoles and condensed imidazoles, are rather uncommon. 6-8 On the other hand, alkyl-or arylsulfinyl or -sulfonyl substituents as leaving groups in electron-deficient heteroaromatic systems have been reported to have reactivity equivalent to, or greater than, that of a chloro group, and many examples concerning the reactivity of electron deficient azines bearing alkylsulfinyl-and -sulfonyl groups, with simple nucleophiles have been reported. 9,10 To the best of our knowledge, however, there is only one recent literature precedent for the use of sulfinyl or sulfonyl substituents as leaving groups on imidazoles. 11 However, only strongly activated imidazoles bearing electron-withdrawing groups were reported to undergo efficient ipso-substitution reactions with a variety of different nucleophiles.During the course of our studies on the development of efficient methodologies that could be readily adapted for the combinatorial and/or parallel synthesis in solution or on solid supports of relevant core structures, 12-16 we focused our attention on the imidazole nucleus. Imidazoles are important pharmacophores, and many biologically active compounds incorporate this moiety into their structures. Particularly interesting, are fused [1,2-a]imidazoles, which have been reported to have antiulcer, antidepressant, antibacterial and T x A 2 synthase inhibitory activities. [17][18][19][20] Recently, innovative protocols for the synthesis of [1,2-a]-fused imidazoles using intramolecular radical ipso-substitution at the C-2 position have been reported, 21,22 and although many efforts have been devoted to the synthesis of, for instance, imidazo[1,2-a]pyridines, 23 there are no literature reports on the synthesis of imidazo[2,1-b][1,3]oxazoles.Herein, we wish to report our findings on the use for the first time of alkylsulfonyl substituents in electron-rich imidazoles, as effective leaving groups in intramolecular nucleophilic ipso-substitution reactions, and their application toward the preparation of a novel class of fused imidazoles. Thus, when thiouronium salts 1, readily available from the corresponding alkyl halide and thiourea in refluxing ethanol, were allowed to react in MeCN Figure ORTEP plot 27 of the molecular structure of 3a with 50% probability ellipsoids Downloaded by...

Solution- and Solid-Phase Parallel Synthesis of 4-Alkoxy-Substituted Pyrimidines with High Molecular Diversity

“…With the aim of extending the scope of this methodology and in connection with our ongoing projects regarding the development of efficient methodologies that could be readily adapted for the combinatorial or parallel synthesis in solution or on solid supports of relevant core structures with a high degree of molecular diversity, − we decided to study the use of readily available 2-mercaptopyrimidinones of type 2 as potential versatile precursors toward the synthesis on solid support of libraries of different molecularly diverse pyrimidines in a parallel array. Pyrimidines represent an interesting pharmacophore widely distributed on natural and on synthetic products that display an ample variety of relevant biological properties. , For that reason, already several methodologies based on known solution procedures toward the synthesis of pyrimidines with different substitution patterns have been successfully adapted to the solid phase. − A relatively little explored class of pyrimidines, however, are those bearing an alkoxy moiety at the 4-position.…”

Rapid Parallel Synthesis of Combinatorial Libraries of Substituted 3-Thio-1,2,4-triazoles and 2-Thioimidazoles

“…Compounds of the type shown in Figure have been synthesized in the past via a variety of methods. − Although most of these routes were satisfactory for the synthesis of small numbers of compounds, we required a synthetic method for the synthesis of 2-thioimidazoles and 3-thio-1,2,4-triazoles that could be amenable to a high-throughput parallel synthesis protocol. The method should be efficient and convergent and should require minimum manipulation and modification.…”