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).

In Situ Reaction Monitoring of Unstable Lithiated Intermediates through Inline FTIR Spectroscopy

“…Concerning laboratory experiments, many authors successfully synthesized a variety of organolithium compounds within microstructured devices, by taking advantage of precisely adjustable reaction conditions to easily control those highly exothermic and fast reactions [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Key examples are studies by the groups of Yoshida, Feng, and Browne, as shown below.…”

Temperature‐Controlled Base‐Promoted Cyclization for the Synthesis of 2‐Amino‐4H‐benzo[d][1,3]thiazin‐4‐ones and 2‐Thioxo‐4(3H)‐quinazolinones

“…Various methods have been reported for the synthesis of both 2‐thioxo‐2,3‐dihydroquinazolin‐4(1 H )‐ones and 2‐amino‐4 H ‐benzo[ d ][1,3]thiazin‐4‐ones . In general, these valuable frameworks are synthesized from anthranilic acid derivatives and isothiocyanates under harsh conditions.…”

“…For 2‐thioxo‐2,3‐dihydroquinazolin‐4(1 H )‐ones, low yields of around 50 % are often obtained. Recently, Tim and co‐workers reported a concise continuous‐flow integrated synthesis of S‐benzylic thioquinazolinone derivatives in overall excellent yields . Although several other methods have been developed, long synthetic routes, toxic reagents, or a lack of available substrates have limited them from wider application.…”

Towards Versatile Continuous‐Flow Chemistry and Process Technology Via New Conceptual Microreactor Systems

“…Various s ‐benzylic thioquinazolinone derivatives were synthesized within 10 s in high yields at room temperature. Also the interesting thing about this methodology is that three steps involved two organolithium intermediates, an isothiocyanate‐functionalized aryllithium intermediate, and a subsequent lithium thiolate intermediate were conducted by one‐flow and sequential operation (Figure ) …”