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.

One‐pot multicomponent reactions have gained significant importance in recent years because they are usually more selective, simple, efficient, atom‐economic and green than their multistep counterparts. The Betti synthesis involves the combination of aldehydes, amines and 2‐naphthol to form compounds which can serve as catalysts or as biologically active compounds. In this study, Montmorillonite K30 was used as a heterogeneous catalyst for the Betti reaction at 60 °C in relatively short reaction times. Positively, it is cheap, readily and commercially available and requires no preparation, it can be used in neat conditions whilst minimizing excess reagent amounts. Most importantly, it is fully recoverable and can be recycled up to 5 times. In reactions involving secondary aliphatic amines, very good to excellent results were obtained whilst primary ones including benzylamine gave appreciable yields. In addition, the heteroaromatic aldehyde 4‐pyridinecarboxaldehyde and the polyaromatic aldehyde 1‐naphthaldehyde also gave encouraging results.

Imines and their derivatives are of great interest to organic synthetic chemists due to their involvement as key intermediates which facilitate the construction of nitrogen heterocycles, particularly the formation of alkaloids. Imine formation by condensation of primary amines with aromatic aldehydes and cyclohexanone has been investigated under environmentally-friendly solventless heterogeneous catalysis. An array of different imines was obtained in excellent yields in appreciably short reaction times using Amberlyst® 15 as a heterogeneous catalyst. The latter was used owing to its high commercial availability, recyclability, ease of separation from the reaction mixture, and versatility.

Betti bases (aminobenzylnaphthols) have not been studied extensively to explore their possible pharmacological applications. Our group prepared a small and focused library of twenty-three Betti bases from the multicomponent reaction of 2-naphthol with primary or secondary cyclic amines and representative aromatic aldehydes. The compounds were prepared in 52-90% yield using environmentally friendly procedures. The E-factor and the atom economy for our process were 3.92 and 94%, respectively. The study of the anti-proliferative activity against human solid tumor cell lines pointed out that these Betti bases represent privileged scaffolds and could be used for the development of pharmacologically-active compounds in cancer therapeutics. The 50% growth inhibitory (GI 50 ) values of the most potent compounds were in the low micromolar range. Fourteen of these Betti bases were less active in HBL-100 breast cancer cells than towards the breast cancer cell line T-47D. A subset of these Betti bases was further tested against the human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a correlation in the sensitivity of T-47D cells to Betti bases. We explored computationally the interaction of the Betti bases with SLC6A14, a Na + -and Cl − -dependent influx transporter of both neutral and cationic amino acids that is overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan, which blocks cell growth via deprivation of amino acid influx. The docking studies indicated that our Betti bases might behave as tryptophan mimetics, blocking this solute carrier transporter and inducing the anti-proliferative effects. Importantly, these Betti bases showed good cytotoxic selectivity towards cancer cells with no activity against normal human fibroblast cells BJ-hTERT.

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