Synthesis of hexahydro-1H-pyrrolo[1,2-c]imidazole derivatives by sequential azomethine ylide cycloaddition and urea cyclization reactions (original) (raw)
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The Journal of Organic Chemistry, 2005
A simple and efficient one-pot, three-component synthesis of highly functionalized pyrrolidines via cascade imine f azomethine ylide f 1,3-dipolar cycloadditions is reported. Admixing a variety of aldehydes, dimethyl 2-aminomalonate, and electron deficient alkenes in THF leads to the clean production of pyrrolidines in good to excellent yields. The mild reaction conditions enabled the generation of previously inaccessible azomethine ylides from enolizable aldehydes. Endo selectivity was exclusive with N-phenyl maleimide and maleic anhydride. Good chemo-, regio-, and stereoselectivities were observed with methyl acrylate, though catalysis by Ag(I) was necessary with this dipolarophile. FIGURE 1. Inspiration for the current study.
A revised approach to the synthesis of 3-acyl imidazo[1,2-a] pyridines
Heterocyclic Communications, 2010
3-Acyl imidazo[l,2-a]pyridines with no substituent at position 2 were obtained in moderate to good yields in an improved version of the Tisler protocol for the synthesis of imidazo[l,2-x]azines. It was found that yields are significantly improved if the reaction is carried out in the presence of DMF or in some cases in the absence of a solvent. INTRODUCTION The fused heterocyclic system imidazo[l,2-a]pyridine is an important pharmacophore, as is demonstrated by the broad variety of pharmacological activities shown by its derivatives.' The most common approach to the synthesis of the imidazo[l,2-o]pyridine ring is based on the condensation reaction of 2-aminopyridines with a-halocarbonyl compounds. 2 This methodology allows the direct construction of 2 or 2,3-substituted imidazo[l,2-a]pyridines, but is not usefiil for the synthesis of 3-acyl imidazo[l,2-a]pyridines with no substituent at position 2. The interesting aspect of 3-aroyl imidazo[l,2-a]pyridines is their potential biological activity. Thus, derivatives of 2-amino-3-aroyl imidazo [l,2-a]pyridines have been evaluated as antiviral agents. 3 A useful method of synthesis of 3-acyl imidazo[l,2-a]azines is the intramolecular cyclization of alkylated iV-heteroaryl formamidines, described by Tisler. 4,5 Direct thermal regiospecific acylation of 7-methyl imidazo[l,2-a]pyridine has also been reported. 6 Since our research program required 3-aroyl imidazo[l,2-a]pyridines unsubstituted at position 2 to carry out several studies, the Tisler method was the best option to synthesize them. However, in the Tisler protocol the related derivative 2-methyl-3-benzoylimidazo[l,2-a]pyridine 2 was obtained in only 16% yield via condensation of formamidine 1, with the corresponding α-bromoketone. The results of an adaptation of such methodology to the synthesis of 3-acyl imidazo[l,2-a]pyridines unsubstituted at position 2 are presented herein. RESULTS AND DISCUSSION The study began with a multicomponent approach to the 3-acyl imidazo[l ,2-a]pyridine heterocyclic system, employing 2-aminopyridine, 2-bromoacetophenone and formaldehyde. However, from this experiment only 2-phenylimidazo[l,2.a]pyridine was obtained. Then DMFDMA, a well known one carbon synthon useful in the synthesis of heterocycles, 7 was used in place of formaldehyde. This attempt was also unsuccessful, giving only traces of 3-(4'-chlorobenzoyl imidazo[l,2-a]pyridine. Therefore, it was decided to directly treat the jV'-pyridylformamidine 3
Azomethine Ylides—Versatile Synthons for Pyrrolidinyl-Heterocyclic Compounds
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Azomethine ylides are nitrogen-based three-atom components commonly used in [3+2]-cycloaddition reactions with various unsaturated 2π-electron components. These reactions are highly regio- and stereoselective and have attracted the attention of organic chemists with respect to the construction of diverse heterocycles potentially bearing four new contiguous stereogenic centers. This review article complies the most important [3+2]-cycloaddition reactions of azomethine ylides with various olefinic, unsaturated 2π-electron components (acyclic, alicyclic, heterocyclic, and exocyclic ones) reported over the past two decades.
Tetrahedron, 2006
The 1,3-dipolar cycloaddition of dimethyl acetylenedicarboxylate with nonstabilized azomethine ylides, generated via the decarboxylative condensation of 1,3-thiazolidine-4-carboxylic acids with aldehydes, afforded 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazole derivatives. 2-Substituted-1,3-thiazolidine-4-carboxylic acids led to the stereoselective formation of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles. Quantum-chemistry calculations were carried out allowing the rationalization of the observed stereoselective formation of the anti-dipole.