Title:Application of Design of Experiments (DoE) Approach for the Optimization of Phase-transfer Catalyzed Biginelli Dihydropyrimidinone (DHPM) Synthesis
Volume: 18
Issue: 7
Author(s): T. Durai Ananda Kumar*, N. Swathi, C.V.S. Subrahmanyam and K. Satyanarayana
Affiliation:
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education & Research, SS Nagara, Mysuru, 570 015, Karnataka,India
Keywords:
Domino process, Phase-transfer catalyst, Biginelli reaction, 3, 4-Dihydropyrimidin-2-(1H)-ones, Factorial design.
Abstract: The conventional Biginelli synthesis is more cumbersome and produces lower yields. Several
improved methods are reported in the literature to replace the Biginelli catalyst. The design of biocompatible
organic transformation is a major concern and a versatile greener procedure to construct
Biginelli analogs is in great demand. Factorial design guided, energy-efficient, and versatile synthesis
of 3,4-dihydropyrimidin-2-(1H)-ones (DHPM) was developed. One-factor-at-a time (OFAT) and factorial
design (23) studies were utilized for screening the independent variables. The optimum levels of
potential variables (benzyl-n-triethylammonium chloride (BTEAC) and glacial acetic acid) were determined
through studies. The factorial design (32) analysis inferred the use of BTEAC (10.25 mol%)
and glacial acetic acid (7.6 ml) as optimal for the 60 min condensation. Thirteen new 3,4-
dihydropyrimidine-2-(1H)-one (DHPM) analogs were synthesized using optimized reaction conditions.
The quaternary ammonium ion of BTEAC stabilizes the polarization of carbonyl group in aryl aldehydes
and enolizable ketone (alkyl acetoacetate) to facilitate the cyclocondensation, in order to produce
DHPMs through N-acyliminium ion and Michael adducts formation. The biocompatible strategy, simple
product isolation (non-chromatographic method), and good to excellent yields are attractive features of
this new protocol. Hence, the newly developed methodology is superior to the literature methods.
