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N-Heterocycles
Published in Navjeet Kaur, Metals and Non-Metals, 2020
Pyrroles are an important class of heterocycles and are widely used in material science and synthetic organic chemistry. Extensive investigations have been made to develop procedures for the synthesis of substituted pyrroles for their distinctive properties. The 1,2,3,4-tetrasubstituted pyrroles are synthesized by Knorr reaction [19], Hantzsch pyrrole synthesis [20], or 1,3-dipole addition of azomethyne ylides with alkynes [21–25]. Classical methods to obtain pyrrole derivatives also involve condensation reactions of 1,4-dicarbonyl reactants [26–27]. This procedure of synthesizing pyrrole derivatives is adapted using ionic liquids [bmim]BF4 [28] for the condensation reaction of primary amines and 1,4-dicarbonyl reactants. The ionic liquid is utilized in a molar ratio of 1:16 (reactant/IL) and is recovered and reused four times with only a gradual decrease in activity (87%, 85%, 81%, and 76% yields). The reaction occurs smoothly in ionic liquids as well as in refluxing toluene in the presence of 5 mol% Bi(OTf)3. For these condensation reactions, Bi(OTf)3/[bmim]BF4 has been found to be the ideal catalytic system. Moreover, the recovery and reuse of Bi(OTf)3 is especially easy in ionic liquids than in toluene. Although the reaction in ionic liquid includes a catalyst, Bi(OTf)3, it is considered faster and more convenient than I2-catalyzed reactions using molecular solvents like CH2Cl2 or tetrahydrofuran (20 h at rt) (Scheme 3) [29, 30].
Benign synthesis of therapeutic agents: domino synthesis of unsymmetrical 1,4-diaryl-1,4-dihydropyridines in the ball-mill
Published in Green Chemistry Letters and Reviews, 2022
Cristina Blazquez-Barbadillo, Juan Francisco González, Andrea Porcheddu, David Virieux, José Carlos Menéndez, Evelina Colacino
Nowadays, the combination of enabling technologies with synthetic strategies and processes ‘benign by design’ and characterized by minimal waste generation represents a powerful approach to address the quest for a sustainable organic chemistry. In this context, synthetic strategies combining tandem, domino or cascade (1, 2), with multicomponent reactions (3) (MCR) have attracted increasing attention, being usually characterised by step and intrinsically high atom, step and pot economy while generating structural complexity and molecular diversity with operational simplicity and waste minimization. The efficiency and the low ecological footprint of these powerful synthetic tools can be additionally improved by conducting the reactions using mechanochemistry, an environmentally friendly technology closely intertwined with the 12 principles of Green Chemistry (4,5). The low environmental impact displayed by mechanochemical processes has been recently demonstrated for the preparation of Active Pharmaceutical Ingredients (APIs) by life cycle assessment studies in the continuous flow mechanochemical manufacturing of nitrofurantoin (6), and its quantitative assessment against the 12 principles of green chemistry by using the DOZN 2.0 tool (7). Therefore, the possibility to access complex biologically relevant structures and value-added compounds from simple precursors by mechanochemical domino or multicomponent reactions is very appealing (8). Mechanochemically-activated synthetic approaches to heterocyclic systems were previously reported for both: (i) domino or cascade reactions to prepare dihydropyrroles and pyrroles (via oxidative cyclocondensation reactions) (9), pyrazolones and isoxazolones (by asymmetric organocatalytic Mannich reaction-fluorination) (10), indolylquinones (by Michael addition-oxidation sequence) (11), and (ii) multicomponent reactions to access pyrroles (by Hantzsch pyrrole synthesis) (12, 13), thiophenes (by Gewald reaction) (14), coumarine thiazolidinones (15), 4H-chromene derivatives (16), dihydropyrimidones (17) and 2,3-dihydro-1,2,6-thiadiazine 1-oxides (18) (by Biginelli-type reaction), benzoxazines (by condensation/Mannich base ring-closure reactions) (19), α-amino phosphonate derivatives (by Kabachnik-Fields reaction) (20), or peptidic-like adducts (by Ugi 4-CR) and α-acyloxy amides (by Passerini-3CR) (21).