Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

Abstract

Here we report the generation of a small focused library of 12 diversely functionalized dihydropyrimidine (DHPM) derivatives via one-pot three-component Biginelli cyclocondensation of b-ketoesters, aldehydes and (thio)ureas. By applying controlled microwave heating under sealed vessel conditions using a fully automated microwave instrument including a gripper and liquid handler, the sequential synthesis of DHPMs can be performed in a shorter reaction time (10-20 min per one DHPM derivative) compared to conventional heating methods, which normally require several hours of reflux heating. The solid products either crystallize directly upon cooling or can be precipitated upon addition of water, requiring only filtration for isolation. In this way, the DHPM derivatives are obtained in high purity and no further purification by recrystallization or chromatography is necessary. This can be ascribed to the microwave heating technology where less side-product formation is often seen. The preparation of this 12-membered DHPM library can be carried out within B9 h.

Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

“…Compounds 1 were used as a limiting agent to react with urea/thiourea 2 and acetylacetone 3 for the Biginelli reactions. The reactions were promoted by Yb(OTf) 3 as a catalyst [14–15], acetonitrile as a solvent, and under microwave irradiation at 120 °C for 20 min. This optimized condition was developed after other solvents, including water, EtOH and toluene, and different microwave reaction temperatures (100–130 °C) and times (10–20 min) were explored.…”

Experimental Protocols

“…Yield and physical data See Literature [31] Background The Biginelli synthesis, the cyclocondensation of b-keto esters, aldehydes and (thio)urea, is another MCR useful for generating libraries relevant to medicinal chemists which is exceptionally flexible in creating chemical diversity about the dihydropyrimidine (DHPM) scaffold. This protocol for the synthesis of a 12-membered DHPM library under fully automated conditions was taken from a literature example [31].…”

“…This protocol for the synthesis of a 12-membered DHPM library under fully automated conditions was taken from a literature example [31]. The preparation of this library including work-up can be carried out within about 9 h. Background The Biginelli library generation using sequential techniques has been reported [32], and the current example adapts these conditions for parallel processing.…”

“…31 Reagents and hazard information for the ethoxycarbonylation. irritating to eyes, respiratory system and skin; may be harmful if inhaled, swallowed, or absorbed through skin1,8-diazabicyclo[5.4.0]undec-7-ene [6674-22-2] 4 · 1.1 656 mL a corrosive; harmful if swallowed; causes burns; harmful to aquatic organisms; may cause long-term adverse effects in the aquatic environment; unpleasant odor irritant; causes severe eye irritation; risk of serious damage to eyes; may be harmful if inhaled, swallowed, or absorbed through skin ethanol [64-17-5] 40 mL a flammable; irritant; irritating to eyes, respiratory system and skin; target organs: nerves, liver chloroform [67-66-3] 500 mL harmful by ingestion; irritant; carcinogen; target organ effect; target organs: central nervous system, blood, liver, cardiovascular system, kidney a For a better handling due to the very low catalyst loading a stock solution containing 1.64 mL DBU, 2.3 mg Pd(OAc) 2 and 100 mL EtOH can be prepared.…”

Ultrasound‐Assisted Synthesis of Novel Pyrrole Dihydropyrimidinones in Lactic Acid

“…Much attention has been focused on using different Lewis acid catalysts such as Yb(OTf) 3 , BF 3 , InCl 3 , LaCl 3 , etc. in solution, in ionic liquid or in the absence of solvent . However, the organic solvents and the catalysts which are widely used for organic reactions have brought serious pollution to the environment.…”