The Groebke-Blackburn-Bienayme Reaction

Imidazo[1,2a]pyridine is a well‐known scaffold in many marketed drugs, such as Zolpidem, Minodronic acid, Miroprofen and DS‐1 and it also serves as a broadly applied pharmacophore in drug discovery. The scaffold revoked a wave of interest when Groebke, Blackburn and Bienaymé reported independently a new three component reaction resulting in compounds with the imidazo[1,2‐a]‐heterocycles as a core structure. During the course of two decades the Groebke Blackburn Bienaymé (GBB‐3CR) reaction has emerged as a very important multicomponent reaction (MCR), resulting in over a hundred patents and a great number of publications in various fields of interest. Now two compounds derived from GBB‐3CR chemistry received FDA approval. To celebrate the first 20 years of GBB‐chemistry , we present an overview of the chemistry of the GBB‐3CR, including an analysis of each of the three starting material classes, solvents and catalysts. Additionally, a list of patents and their applications and a more in‐depth summary of the biological targets that were addressed, including structural biology analysis, is given

9-(1H-Benzo[d]imidazol-2-yl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline

The title compound, C19H19N3, is a 2-heteroaryl benzimidazole derivative obtained through a straightforward and efficient protocol starting from julolidine-9-carbaldehyde and 1,2-phenylendiamine. The mean planes of the heterocyclic moieties in the molecule, benzimidazole and julolidine, form a dihedral angle of 40.9 (1)°. In the crystal, N—H...N hydrogen bonds link the imidazole rings, forming chains along the c-axis direction

Synthesis of Imidazo[1,2-a]pyridine-Chromones via Microwave-Assisted Groebke-Blackburn-Bienaymé Reaction

A series of imidazo[1,2-a]pyridine-chromones were synthesized by microwave-assisted Groebke–Blackburn–Bienaymé reaction (GBBR) under eco-friendly conditions (20 mol% ammonium chloride catalyst in EtOH). Chromones and imidazo[1,2-a]pyridines are a privileged core of high interest in medicinal chemistry

Synthesis of 1,2,3-Triazoles from Alkyne-Azide Cycloaddition Catalyzed by a Bio-Reduced Alkynylcopper (I) Complex

A small library of 1,2,3-triazoles was synthesized from diverse alkynes and azides using catalytic amounts of an alkynylcopper (I) complex, which in turn was prepared from direct treatment of phenylacetylene with a Fehling reagent in the presence of glucose as a reducing agent. The results suggest that copper-catalyzed azide alkyne cycloaddition (CuAAC) reactions require only 0.5 mg/mmol copper (I) phenylacetylide without any further additives

A One-Pot Process for the Synthesis of Alkyne-3-tretrazolyl-tetrazolo [1,5-a] Quinolines

An efficient synthesis of alkyne-3-tetrazolyl-tetrazolo[1,5-a] quinolones via a one-pot isocyanide-based multicomponent reaction (IMCR) process: I-MCR Ugi-azide/SNAr/ring-chain azido tautomerization was performed under eco-friendly conditions. We report the one-pot synthesis of tris-heterocycles containing a tetrazolo[1,5-a] quinoline connected to a 1,5-disubstituted-tetrazole (1,5-DS-T). The synthesis of these compounds is of great interest in synthetic and medicinal chemistry because these heterocycles are considered privileged scaffolds and their preparation and evaluation may lead to the discovery of novel bioactive molecules

Solvent-Free Synthesis of Imidazo [1,2-a] pyridin-tetrazolo [1,5-a] Quinolines via an IMCR One-Pot Process

A solvent-free and catalyst-free synthesis of fused bis-heterocycles containing imidazo[1,2-a]pyridine and tetrazolo[1,5-a]quinoline frameworks is reported via a one-pot process. This Groebke–Blackburn–Bienaymé reaction (GBBR)/SNAr/ring-chain azido tautomerization cascade proceeds under eco-friendly conditions. The tetrazolo[1,5-a]quinoline and imidazo[1,2-a]pyridine scaffolds are present in various compounds with interesting pharmacological properties and could lead to the discovery of novel bioactive molecules

Microwave-Assisted Asinger Synthesis of Thiazolines

An array of 2,4-disubstituted thiazolines was obtained through Asinger reaction approach from the straightforward treatment of diverse aldehydes/ketones with 1-mercaptopropan-2-one, in the presence of NH3 assisted by microwave irradiation, displaying similar and sometimes higher yields, as well as shorter reaction times that traditional Asinger reaction conditions at room and lower temperatures

<i>N</i>-(<i>p</i>-Toluenesulfonyl)-1-(4′-acetylphenoxy)acrylimidate: Synthesis, Crystal Structure and Theoretical Studies

The formation of N-sulfonyl-1-aryloxy acrylimidate is described, for the first time, from a consecutive process, which involves a CuAAC reaction, a ketenimine formation and subsequent rearrangement between an aryl propargyl ether and a sulfonyl azide. The structure of this newly synthesized compound was analyzed by NMR spectra and unambiguously established by X-ray analysis. In addition, theoretical calculations, which included a Hirshfeld surface, FMO, QTAIM and NCI indices analysis, corroborated the formation of π-π stacking interactions among aromatic rings, as well as C-H···O interactions between vinyl hydrogens with ketone carbonyl oxygen

Multicomponent One-Pot Synthesis of 3‑Tetrazolyl and 3‑Imidazo[1,2‑<i>a</i>]pyridin Tetrazolo[1,5‑<i>a</i>]quinolines

A series of 18 3-tetrazolyl-tetrazolo­[1,5-<i>a</i>]­quinolines were synthesized in 21–90% yields via a novel one-pot Ugi-azide/S_NAr/ring–chain azido-tautomerization process. We report also the synthesis of 10 3-imidazo­[1,2-<i>a</i>]­pyridin-tetrazolo­[1,5-<i>a</i>]­quinolines in 28–94% yields via a novel one-pot Groebke–Blackburn–Bienaymé/S_NAr/ring–chain azido-tautomerization process. Both synthetic strategies involve the use of microwaves or ultrasound, and catalyst-free conditions. Finally, we show the synthesis of the tetrazolo­[1,5-<i>a</i>]­quinoline-3-carbaldehyde and tetrazolo­[1,5-<i>a</i>]­quinoline-3-dimethyl acetal at room temperature in methanol as solvent