Microwave-assisted 1,2-dihydropyridine synthesis

Li M, Zuo Z, Wen L et al (2008) Microwave-assisted combinatorial synthesis of hexa-substituted 1,4-dihydropyridines scaffolds using one-pot two-step multi-component reaction followed by a S-alkylation. J Comb Chem 10 436-441... 

The Hantzsch dihydropyridine synthesis has been performed [75] in a singlemode microwave cavity. In comparison with both conventional methods and microwave-assisted reactions performed in a domestic oven, reaction times were shorter and yields were higher (Scheme 8.51). 

A one-pot synthesis of N-substituted 4-aryl-l, 4-dihydropyridines using a microwave-assisted procedure was described in 2001 (Scheme 10.97) [187]. Among a variety of solid supports (Kio, acidic alumina, zeolite HY, silica gel), silica gel was proved to be the most efficient. After irradiation for 4 min, the reactions led to yields ranging from 62 to 94%. 

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines (1,4-DHP) was reported in 2003 [195]. The experimental method proposed more than a century ago remains the most widely used for synthesis of these heterocycles. Since 1992 the process has been adapted to microwave irradiation under a variety of conditions to reduce the reaction time and enhance the yield. Among these experiments, Zhang reported a solvent-free process starting from 3-aminocrotonate (20 mmol), methyl acetoacetate (20 mmol), and aromatic aldehydes (20 mmol) in a domestic oven [196]. Yields from 59 to 77% were reported for 10-min reaction. A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP. Only procedures involving solvent-free conditions under the action of microwave irradiation led to the aromatized pyridine derivatives. 

For example, a bioinspired oxidation with hydroperoxy-flavins 590 combined with a catalyst-free 1,4-dihydropyri-dine synthesis effectively produces C4-unsubstituted pyridines 591 (Scheme 13.147) [267], whereas a palladium on carbon oxidation combined with an MK-10 catalyzed 1,4-dihydropyridine formation under microwave assistance reduces the reaction time (Scheme 13.148) [268]. A one-pot performance of the pyridine synthesis is also possible in water with stoichiometric soluble oxidants like iron chloride or potassium permanganate (Scheme 13.148) [266]. Nevertheless, both examples (Scheme 13.148) cleave off... 

Singh et al. (2008) studied a microwave-assisted [4+2] cycloaddition reaction for the synthesis of unsymmetrically substituted 1,4-dihydropyridines. 1,4-Dihy-dropyridine analogs such as Nifedipine and Nimodipine are well known for their potent biological activities. Microwave-assisted [4+2] cycloaddition of 1,4-diaryl-1-aza-1,3-butadienes with allenic esters at 100°C for 5-17 min gave cycloadducts in excellent yields (83-96%), which after a tandem 1,3-H-shift furnished unsymmetrically substituted 1,4-dihydropyridines. 

A rapid synthesis of 1,4- dihydropyridine was achieved by microwave-assisted aza-Diels-Alder reaction (Lee and Kim, 2011). 

A microwave dielectric heating assisted TSIL phase synthesis [45] of 1,4-dihydropyridines, 3,4-dihydropyrimidin-2(lH)-ones, pyridines and polyhydroquinolines using a TSIL as a soluble support was described. The efficiency of the ionic liquid phase organic synthesis (loLiPOS) methodology was demonstrated by using a one-pot three-component condensation. The stmcture of the intermediates... 

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