Diversity in Heterocycle Synthesis Using α-Iminocarboxylic Acids: Decarboxylation Dichotomy.

Despite the structural similarity with imines, α-iminocarboxylic acids have seldom been used in heterocycles synthesis. The reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40 °C gave various benzo-fused five- to six-membered N-heterocycles in good to excellent yields. The reaction proceeds via intramolecular Michael addition of α-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, yielding an isolable unprecedented tetrahedral carboxylic acids, which upon decarboxylation without any aid of additional reagents forms the N-heterocycles. DMSO is crucial in this reaction, perhaps because of improved solubility and the ease of decarboxylation of these tetrahedral carboxylic acids. However, a copper-catalyzed reaction of ortho-substituted anilines and 2-bromoarylglyoxylic acids gave a dibenzo-fused seven-membered N-heterocycle under a basic reaction condition. Unlike intramolecular cyclization with α-iminocarboxylic acids in the first case, α-iminocarboxylic acid undergoes a competitive decarboxylation under the copper-catalyzed conditions, which upon subsequent heteroarylation form the heterocycles. Taken together, the study described herein represents two different modes of decarboxylation observed with α-iminocarboxylic acids, leading to the synthesis of divergent heterocycles and pharmaceuticals, which remained unexplored previously.

K2S2O8 activation by glucose at room temperature for the synthesis and functionalization of heterocycles in water.

While persulfate activation at room temperature using glucose has primarily been focused on kinetic studies of the sulfate radical anion, the utilization of this protocol in organic synthesis is rarely demonstrated. We reinvestigated selected K2S2O8-mediated known organic reactions that invariably require higher temperatures and an organic solvent. A diverse, mild functionalization and synthesis of heterocycles using the inexpensive oxidant K2S2O8 in water at room temperature is reported, demonstrating the sustainability and broad scope of the method. Unlike traditional methods used for persulfate activation, the current method uses naturally abundant glucose as a K2S2O8 activator, avoiding the use of higher temperature, UV light, transition metals or bases.

Recent Advances in Functionalization of Pyrroles and their Translational Potential.

Among the known aromatic nitrogen heterocycles, pyrrole represents a privileged aromatic heterocycle ranging its occurrence in the key component of "pigments of life" to biologically active natural products to active pharmaceuticals. Pyrrole being an electron-rich heteroaromatic compound, its predominant functionalization is legendary to aromatic electrophilic substitution reactions. Although a few excellent reviews on the functionalization of pyrroles including the reports by Baltazzi in 1963, Casiraghi and Rassu in 1995, and Banwell in 2006 are available, they are fragmentary and over fifteen years old, and do not cover the modern aspects of catalysis. A review covering a comprehensive package of direct functionalization on pyrroles via catalytic and non-catalytic methods including their translational potential is described. Subsequent to statutory yet concise introduction, the classical functionalization on pyrroles using Lewis acids largely following an ionic mechanism is discussed. The subsequent discussion follows the various metal-catalyzed C-H functionalization on pyrroles, which are otherwise difficult to implement by Lewis acids. A major emphasize is given on the radical based pyrrole functionalization under metal-free oxidative conditions, which is otherwise poorly highlighted in the literature. Towards the end, the current development of pyrrole functionalization under photocatalyzed and electrochemical conditions is appended. Only a selected examples of substrates and important mechanisms are discussed for different methods highlighting their scopes and limitations. The aromatic nucleophillic substitution on pyrroles (being an electron-rich heterocycle) happened to be the subject of recent investigations, which has also been covered accentuating their underlying conceptual development. Despite great achievements over the past several years in these areas, many challenges and problems are yet to be solved, which are all discussed in summary and outlook.

Palladium-Catalyzed Serendipitous Synthesis of Arylglyoxylic Amides from Arylglyoxylates and N,N-Dialkylamides in the Presence of Halopyridines.

A palladium-catalyzed synthesis of arylglyoxylic amides by the reaction of arylglyoxylates and N,N-dialkylamides in the presence of a 2,3-dihalopyridine has been realized for the first time. An anticipated 2,3-diaroylpyridine did not form in this reaction. The current study unveils an unprecedented role of 2,3-dihalopyridine toward this amidation. Our mechanistic study reveals that the arylglyoxylate could react with halopyridine to form a traceless activated pyridyl ester of arylglyoxylic acid, which upon subsequent reaction with amino surrogate, N,N-dialkylamides could form the arylglyoxylic amides.

Intramolecular Oxidative Arylations in 7-Azaindoles and Pyrroles: Revamping the Synthesis of Fused N-Heterocycle Tethered Fluorenes.

We revealed intramolecular oxidative arylations in 7-azaindoles and pyrroles that, for the first time, provided direct access to 7-azaindole- or pyrrole-fused isoindolines and tetrahydroisoquinolines. In addition, N-benzylation of 7-azaindoles or pyrroles with sterically hindered sec-benzyl alcohols by Mitsunobu reaction followed by intramolecular oxidative arylation allowed access to chiral congeners of fused isoindolines that have little precedence. A new opportunity in the design and synthesis of fluorene-based organic emitters is demonstrated in the preparation of novel fused N-heterocycle tethered fluorenes, including a chiral fluorene architecture.