A Green Approach to Nucleophilic Aromatic Substitutions of Nicotinic Esters in Cyrene

Abstract

The green solvent CyreneTM has emerged as a valuable substitute for conventional polar aprotic organic solvents such as DMF, DMSO and NMP (renowned for their toxicity and environmental concerns). However, in the presence of bases, Cyrene is prone to polymerization, thus potentially incompatible with reactions where a base is needed to generate reactive nucleophiles. In this study, we developed an efficient synthetic strategy for nucleophilic aromatic substitutions of nicotinic esters in Cyrene. The success of this protocol relies on a very short reaction time (only 15 minutes) which prevents polymerization from occurring. Indeed, Cyrene not only outperformed typical solvents such as DMF and DMSO, but also, being highly soluble in water, allowed an easy purification of the desired products by simple precipitation upon the addition of ice‐water.

Nicotinic Acid Derivatives As Novel Noncompetitive α-Amylase and α-Glucosidase Inhibitors for Type 2 Diabetes Treatment

“…A S N Ar reaction allowed the synthesis of 2−5 and 10−21 pyridyl-phenyl ethers or thioethers through an innovative green synthetic approach recently published by our research group. 12 Briefly, starting compounds A or B were reacted with the appropriate phenol or thiophenol in the presence of NEt 3 as the base using the green solvent Cyrene under heating at 150 °C for 15−30 min in a sealed tube, affording the products 2−5 and 10−21 in good to optimal yields (60−95%). The advantage of this Cyrene-mediated methodology is to avoid the use of toxic and dangerous solvents (such as DMF or DMSO) and reduce reaction times.…”

“…Nicotinic acid, also known as niacin or vitamin B3, is a pyridine derivative showing a plethora of biological activities and therapeutic effects, including lipid-lowering activity, anti-inflammatory effects, vasodilatory effects and treatment of pellagra. − Very recently nicotinic acid derivatives functionalized at position 5 with a thiourea moiety have been proposed as novel interesting α-amylase and α-glucosidase inhibitors . Following our ongoing research about nicotinic acid derivatives, we synthesized a library of 19 novel compounds and tested them for in vitro inhibition of α-amylase and α-glucosidase activity. Our chemical exploration was attempted both to position 5, keeping the hydrogen bond donor (−NH 2 ) as observed in the parental thiourea derivatives or removing it, and position 6 that was modified introducing (thio)ether moieties in order to explore available chemical space (Figure ).…”

“…For the series of 5-amino nicotinic acids, the starting material 6-chloro-5-nitro nicotinic ester (B) was used directly as the methyl ester. A S N Ar reaction allowed the synthesis of 2 – 5 and 10 – 21 pyridyl-phenyl ethers or thioethers through an innovative green synthetic approach recently published by our research group . Briefly, starting compounds A or B were reacted with the appropriate phenol or thiophenol in the presence of NEt 3 as the base using the green solvent Cyrene under heating at 150 °C for 15–30 min in a sealed tube, affording the products 2 – 5 and 10 – 21 in good to optimal yields (60–95%).…”