Heduck Mah

Syntheses of 1,3-Imidazolin-2-Ones and 1,3-Imidazolin-2-Thiones from New Building Blocks, γ-Aminoacetoacetanilides

ReceiVed April 23, 2008 Exploration of new building blocks for the preparation of heterocyclic compound libraries with molecular diversity is an ever-expanding area in combinatorial chemistry. To respond to this demand, new technologies, including multicomponent reactions and click chemistry, have been developed. In our previous paper, we reported that the construction of two different chemical libraries of 1,3imidazolin-2-thione and 2-phenylimino-1,3-thiazoline starting from three building blocks, γ-chloroacetoacetanilides 1, amines, and isothiocyanates. As an expansion of our study for the construction of a new chemical library of heterocyclic compounds, we synthesized new γ-aminoacetoacetanilide derivatives 3 by replacing chlorine in 1 with amino moiety. The γ-aminoacetoacetanilide derivatives 3 would be useful building blocks for preparing new heterocyclic compounds because of their four reactive centers within the molecule. First, the methylene protons are activated by neighboring carbonyl moieties. Second, the amide is an ambient nucleophile by means of the nitrogen and oxygen atoms. Third, the carbonyl of the ketone is susceptive for an addition of nucleophile. Fourth, the primary amine at γ position has good nucleophilic character. In this paper, we report the synthesis of the new building blocks, γ-aminoacetoacetanilide derivatives 3 and the preparations of two different scaffolds, 1,3-imidazolin-2-one 9 and 1,3-imidazolin-2-thione derivatives 10, by the reaction of 3 with isocyanates and isothiocyanates, respectively. 1,3-Imidazolin-2-one and its sulfur analogue, 1,3-imidazolin-2-thione, derivatives have received attention over the past few years because of their interesting biological activities. For example, enoximone and piroximone possess antioxidant, phosphodiesterase, and cardiotonic activities. Others have been shown to exhibit good herbicidal activities, such as imazamethbenz and imazethapyr. There are many known methods for the synthesis of 1,3-imidazolin-2-ones and 1,3-imidazolin-2-thiones, including Marckwald’s method. Recently, the novel synthesis of imidazolin-2thiones was reported by Zeng et al., and their use in organic synthesis was reviewed by Zav’yalov et al. The starting γ-chloroacetoacetanilides 1 were prepared by the same method as previously reported. R-Aminoketones are considerably less well behaved for organic syntheses, as compared to R-aminoesters, because of self-condensation reactions. As shown in Scheme 1, the γ-aminoacetoacetanilides 3 can be prepared easily and efficiently from 1 through a modified procedure of the previously reported method. The reaction of γ-chloroacetoacetanilides 1 with sodium azide in acetonitrile at 40° for 4-6 h gave γ-azidoketone 2 in a quantitative yield. The same reaction at a higher temperature or longer reaction time resulted in low yield of the product. Without purification, treatment of 2 with triphenylphosphine in tetrahydrofuran in the presence of excess amount (3 mol equiv) of p-toluenesulfonic acid monohydrate (p-TSA) at room temperature afforded γ-aminoacetoacetanilides 3 as the p-TSA salts. The structure of 3 was confirmed by the H NMR spectroscopy and the IR spectrometry. For 3a, two singlets at δ 3.71 and 4.08 ppm in the H NMR spectrum and a strong absorption at 3200-3300 cm in the IR spectra were in agreement with the structure. After the supply of 3 was secured, the chemical reactivity and available potentialities for the construction of heterocyclic molecules from 3 were investigated. Because the γ-amino moiety in 3 is a good nucleophile, we decided to react 3 with a good electrophile, such as isocyanate derivatives. The reaction between 3b and o-tolyl isocyanate, which was chosen arbitrarily, proceeded smoothly in the presence of triethylamine at room temperature for 2 h to obtain the desired product 5b (Scheme 2). Acetone was the best solvent of choice for obtaining high yield of 5b. Solvents such as acetonitrile, benzene, methylene chloride, dioxane, dimethylformamide, or ethanol either gave poor yields of 5b or led to the production of side products. Under similar reaction conditions, the γ-aminoacetoacetanilides 3 were subjected to various isocyanate or isothio-

Unexpected formation of pyrrolo[2,1-b]thiazoles by rearrangement of α-hydroxydihydro-1,4-thiazines

A new synthesis of pyrrolo[2,1-b]thiazoles (5) is described. Hydrolysis of acetoxy dihydro-1,4-thiazine (2) prepared by Pummerer reaction of dihydro-1,4-thiazine sulfoxide gave the intermediate α-hydroxy sulfide (4). Dehydration of 4 gave pyrrolo[2,1-b]thiazoles (5). The reaction mechanism for the formation of 5 including the intermediate thiol (6) is discussed.