Development and Scale-Up of a New Sulfone-Based Bismacycle as a Universal Precursor for Bi(V)-Mediated Electrophilic Arylation

• Published in: Organic process research & development Vol. 28; no. 2; pp. 632 - 639
• Main Authors: Fox, Andrew, Ball, Liam T.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.02.2024; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; bismacycle; electrophilic arylation; lithiation; design of experiments; bismuth; transmetalation; PHENYLATION; BISMUTH(III); PHENOLS; ESTERS; CHEMISTRY; PENTAVALENT ORGANOBISMUTH REAGENTS; ENOLS
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.3c00509

The scope and practical utility of bismuth­(V)-mediated electrophilic arylation have been greatly improved by the recent development of user-friendly protocols based on modular bismacycle reagents. Here, we report the scalable synthesis of a new bench-stable bismacycle bromide and demonstrate that it can be used as a “universal precursor” in electrophilic arylation. Relative to established syntheses of related bismacycles, the new protocol benefits from improved step- and vessel-economy, reduced production time, and the complete elimination of cryogenic temperatures and undesirable solvents (Et2O and CH2Cl2). The synthesis is complemented by a robust, chromatography-free purification procedure that was developed by using design of experiments. We show that this process is highly reproducible at the 100 mmol scale, with two independent experiments giving 61 and 62% yields of isolated material. We anticipate that this efficient method for the synthesis of a new bismacycle precursor will expedite both (a) wider uptake of existing bismuth-mediated arylation methods by the synthetic community and (b) ongoing efforts to develop new bismuth-mediated transformations.