Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis

Journal article

Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare catalysts that allow the efficient incorporation of fluorine in organic molecules is therefore essential for broad applicability. Herein, we report a protocol for the multigram synthesis of two representative enantiopure N-alkyl bis-urea organocatalysts derived from (S)-(–)-1,1′-binaphthyl-2,2′-diamine ((S)-BINAM). These tridentate hydrogen bond donors are highly effective phase-transfer catalysts for solubilizing safe and inexpensive metal alkali fluorides (KF and CsF) in organic solvents for enantioselective nucleophilic fluorinations. The first catalyst, characterized by N-isopropyl substitution, was obtained by using a two-step sequence consisting of reductive amination followed by urea coupling from commercially available starting materials (14 g, 48% yield and 5-d total synthesis time). The second catalyst, featuring N-ethyl alkylation and meta-terphenyl substituents, was accessed via a novel, scalable, convergent route that concluded with the coupling between N-ethylated (S)-BINAM and a preformed isocyanate (52 g and 52% overall yield). On this scale, the synthesis requires ~10 d. This can be reduced to 5 d by performing some steps in parallel. Compared to the previous synthetic route, this protocol avoids the final chromatographic purification and produces the desired catalysts in very high purity and improved yield.

Authors: Vicini, AC; Pupo, G; Ibba, F; Gouverneur, V

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Protocols
• Volume: 16
• Issue: 2021
• Pages: 5559–5591
• Publication date: 2021-11-10
• Acceptance date: 2021-08-26
• DOI: 10.1038/s41596-021-00625-y
• EISSN: 1750-2799
• ISSN: 1754-2189
• Language: English
• Keywords: FFR