title: Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates.
abstract: The synthesis of pharmaceutical compounds via short-lived intermediates in a microreactor is attractive, because of the fast flow and high throughput. Additionally, intermediates can be utilized sequentially to efficiently build up a library in a short time. Here we present an integrated microfluidic synthesis of biologically active thioquinazolinone libraries. Generation of o-lithiophenyl isothiocyanate and subsequent reaction with aryl isocyanate is optimized by controlling the residence time in the microreactor to 16 ms at room temperature. Various S-benzylic thioquinazolinone derivatives are synthesized within 10 s in high yields (75-98%) at room temperature. These three-step reactions involve two organolithium intermediates, an isothiocyanate-functionalized aryllithium intermediate, and a subsequent lithium thiolate intermediate. We also demonstrate the gram-scale synthesis of a multifunctionalized thioquinazolinone in the microfluidic device with a high yield (91%) and productivity (1.25 g in 5 min).
authors.affiliation: National Centre of Applied Microfluidic Chemistry, Department of Chemical Engineering, POSTECH (Pohang University of Science and Technology), Pohang, 790-784 (South Korea) http://camc.postech.ac.kr/
authors.forename: Heejin
authors.initials: H
authors.lastname: Kim
authors.forename: Hyune-Jea
authors.initials: HJ
authors.lastname: Lee
authors.forename: Dong-Pyo
authors.initials: DP
authors.lastname: Kim
mesh_terms: D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008094:Lithium / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D052999:Quinazolinones / Q000138:chemical synthesis*
chemical_list: D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D052999:Quinazolinones; D008094:Lithium
keywords: biologically active compounds; microreactors; organolithium compounds; reactive intermediates; thioquinazolinones