One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

Abstract

A rapid route for obtaining unsymmetrical 1,2-dihydropyridines (1,2-DHPs) as opposed to 1,4-dihydropyridines (1,4-DHPs) has been achieved via a one-pot multicomponent Hantzsch reaction. A benign protocol has been developed for the preparation of various 1,2-dihydropyridine derivatives using heterogenized phosphotungstic acid on alumina support (40 wt %). High yields of over 75% have been accomplished in just 2–3.5 h after screening several heterogeneous catalysts and investigating the optimal reaction conditions. The catalyst chosen has passed the heterogeneity test and was shown to have the potential of being reused for up to 8 consecutive cycles before having a significant loss in activity. In addition, aromatic aldehydes gave the aforementioned regioisomer while the classical 1,4-DHPs were obtained when carrying out the reaction using aliphatic aldehydes. The preliminary study of the antiproliferative activity against human solid tumor cells demonstrated that 1,2-DHPs could inhibit cancer cell growth in the low micromolar range.

SBA-15 obtained from rice husk ashes wet-impregnated with metals (Al, Co, Ni) as efficient catalysts for 1,4-dihydropyridine three-component reaction

“…50 It was demonstrated by Shen in 2009 that uncatalyzed Hantzsch reactions resulted in a mixture of 1,2-and 1,4-dihydropyridine regioisomers, in addition to the pyridine resulting from oxidation. 51 Although Bosica et al demonstrated the antiproliferative activity of 1,2-dihydropyridines using a Brønsted acid on alumina support, 52 most of the known bioactivity involves the 1,4-dihydropyridine moiety, such as the commercially available nitrophenyl antihypertensive Nifedipine. Concerning environmentally benign methods, water and ionic liquids as reaction media, microwave irradiation, solid phase synthesis, and green chemistry approaches were also proposed as valuable options for these compounds.…”

Recent Advances in Multicomponent Reactions Catalysed under Operationally Heterogeneous Conditions

“…Although 1,4-DHPs are the usually reported products of the Hantzsch synthesis, the 1,2-isomers can also be synthesized, as was successfully communicated by Bosica et al In this synthetic study (Figure 7) [22], phosphotungstic acid (PW) was heterogenized on alumina before utilising it at room temperature to result in 1,2-DHPs yields ranging between 62 and 94%, obtained in 3.5-6 h. The catalyst could be reused for up to eight consecutive cycles with very minor loss of activity. Instead of DHPs, there are also various studies which have managed to synthesize aromatized pyridines.…”

“…Yields ranged 90-94% when the reactions were performed at 80 °C in acetonitrile solvent for 2.5 h. Positively, the catalyst could be reused for up to five cycles with a three percent reduction in yield between the first and fifth trial [21]. Although 1,4-DHPs are the usually reported products of the Hantzsch synthesis, the 1,2-isomers can also be synthesized, as was successfully communicated by Bosica et al In this synthetic study (Figure 7) [22], phosphotungstic acid (PW) was heterogenized on alumina before utilising it at room temperature to result in 1,2-DHPs yields ranging between 62 and 94%, obtained in 3.5-6 h. The catalyst could be reused for up to eight consecutive cycles with very minor loss of activity.…”

Pelvic Osteotomies in Children and Adults - Experience of University Medical Centre Ljubljana

“…Catalyst was prepared according to the methodology described by Beller et al, (2013), and 1,4-dihydropyridines 4a-c were prepared according to a one-pot multicomponent modification of the methodology reported by Hantzsch (Bosica et al, 2020).…”