Akhilesh Kumar Verma

Biomedical Importance of Indoles

The indole nucleus is an important element of many natural and synthetic molecules with significant biological activity. This review covers some of the relevant and recent achievements in the biological, chemical and pharmacological activity of important indole derivatives in the areas of drug discovery and analysis.

A Copper-Catalyzed Tandem Synthesis of Indolo- and Pyrrolo[2,1-a]isoquinolines†

Transition-metal-catalyzed tandem reactions have emerged as a useful tool for the synthesis of multiring heterocyclic compounds because of the intriguing selectivity, atom economy, and exceptional ability to activate p systems, especially alkynes, towards intermolecular and intramolecular nucleophilic attack. Among the transition-metal-catalyzed reactions, palladium is extensively used because of its tolerance of many functional groups and its low toxicity. However, in recent years copper-catalyzed reactions have received considerable attention because of their efficiency and low costs. 5] The reported annulation chemistry for the synthesis of heterocycles from alkynes proceeds through p complexation of the alkyne and subsequent attack of the resulting h-metal complex onto the appropriate adjacent functionalized arene. 6] However, the synthesis of polyheterocycles by the nucleophilic addition of N heterocycles onto alkynes and subsequent in situ ring closure by C C bond formation is still unknown. Indolo[2,1-a]isoquinolines and pyrrolo[2,1-a]isoquinolines have unique nitrogen-containing tetracyclic and tricyclic structures, and their reduced and oxidized forms occur widely among natural products, biologically active pharmaceuticals, and p-conjugated functional materials, such as organic semiconductors and luminescent materials. The reported methods for the syntheses of indoloand pyrrolo[2,1-a]isoquinolines, typically require multistep syntheses and expensive reagents. Methods for the construction of these structures include well known benzyne reactions or the oxidative couplings of 1-benzylisoquinoline. F rstner and co-workers reported the synthesis of analogous isoquinolines by the cycloisomerization of biaryl alkynes using PtCl2, AuCl, AuCl3, GaCl3, or InCl3. [2a] Herein, we report the first coppercatalyzed synthesis of this class of heterocycles by the tandem addition of N heterocycles onto alkynes and subsequent intramolecular cyclization of the in situ generated enamine by C2 arylation. In continuation of recently developed methods for the copper-catalyzed N-arylation using benzotriazole as a ligand and the electrophilic cyclization of alkynes, 15] we hypothesized that the direct synthesis of polycyclic heteroaromatic compound 6 could occur in a one-pot reaction of N heterocycle 1 with ortho-haloarylalkyne 2 by sequential N C and C C bond formation under the proper conditions such that intermediate 5 would not have to be isolated (Scheme 1, route A). We also anticipated the possible formation of regioisomer 3 by initial arylation of N heterocycle 1 at the C2position by the ortho-haloarylalkyne 2 and subsequent intramolecular attack of the N heterocycle onto the carbon– carbon triple bond of the in situ generated intermediate 4 (Scheme 1, route B). This designed tandem reaction features the use of benzotriazole (L1) and benzotriazol-1-ylmethanol (L2) as novel and inexpensive ligands in copper-catalyzed reactions. To identify the optimal reaction conditions for the reaction, a number of copper catalysts, including CuI, CuCl, CuBr, Cu2O, and Cu(OAc)2, and several different organic solvents and ligands were examined in the reaction of 3methylindole (1a) with 2-bromophenyl-4-methoxyphenylethyne (2a ; Table 1). Interesting observations emerge from the data in Table 1. We first reacted 1 a (0.5 mmol) with 1.1 equivalents of 2a, 10 mol% of CuI, and 1.4 equivalents of KOtBu in 1.0 mL of DMF at 110 8C for 24 hours—the desired coupling product 3a was not observed (Table 1, entry 1). However, the addition of 20 mol% of ligand L1 to the reaction afforded the desired product 3a in a 65 % yield (Table 1, entry 2). The designed ligand L2, was subsequently found to be more effective than ligand L1 (Table 1, entry 3), and from entries 4 and 5 in Table 1 it is apparent that the solvent has a significant influence on the reaction. DMSO was found to be quite successful for the transformation as compound 3a was obtained in an 82 % yield when DMSO was used as the solvent instead of DMF (Table 1, entry 4). When we used toluene as the solvent, the desired product 3a was obtained in only a 38% yield (Table 1, entry 5). Different bases were tested in this reaction system, but KOtBu proved to be most effective (Table 1, entries 4, 6, and 7). The yield of [*] Dr. A. K. Verma, J. Singh, Dr. V. Tandon Dr. B. R. Ambedkar Center for Biomedical Research University of Delhi, Delhi 110007 (India) E-mail: averma@acbr.du.ac.in

An efficient synthesis of 1,5-benzadiazepine derivatives catalyzed by silver nitrate

2,3-Dihydro-1H-1,5-benzadiazepines are synthesized by the condensation of o-phenylenediamine and various ketones in the presence of silver nitrate under solvent-free conditions.

Benzotriazole and Its Derivatives as Ligands in Coupling Reaction

Abstract Download full-size image Benzotriazole-based inexpensive and air-stable bidentate ligands were synthesized for the copper/palladium-catalyzed C C (Suzuki, Heck, Oxidative Heck, and Sonogashira), C N, and C S coupling reactions. Donor ability of N xa0=xa0 N of benzotriazole ring enhance the bidentate ability of the designed ligands. The simplicity, low cost, and ready accessibility in multi-gram scale made these ligands efficient for the coupling reactions. Designed ligands efficiently catalyzed C N, C S, and C C coupling reactions and tolerate variety of functional groups.