Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, 466-8555, Japan.
Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, 466-8555, Japan.
Nat Commun. 2023 Apr 3;14(1):1847. doi: 10.1038/s41467-023-37466-0.
C-N bond cross-couplings are fundamental in the field of organic chemistry. Herein, silylboronate-mediated selective defluorinative cross-coupling of organic fluorides with secondary amines via a transition-metal-free strategy is disclosed. The cooperation of silylboronate and potassium tert-butoxide enables the room-temperature cross-coupling of C-F and N-H bonds, effectively avoiding the high barriers associated with thermally induced S2 or S1 amination. The significant advantage of this transformation is the selective activation of the C-F bond of the organic fluoride by silylboronate without affecting potentially cleavable C-O, C-Cl, heteroaryl C-H, or C-N bonds and CF groups. Tertiary amines with aromatic, heteroaromatic, and/or aliphatic groups were efficiently synthesized in a single step using electronically and sterically varying organic fluorides and N-alkylanilines or secondary amines. The protocol is extended to the late-stage syntheses of drug candidates, including their deuterium-labeled analogs.
C-N 键交叉偶联在有机化学领域中具有重要意义。在此，我们揭示了一种无过渡金属策略，通过硅基硼酸酯介导的有机氟化物与仲胺的选择性脱氟交叉偶联反应。硅基硼酸酯和叔丁醇钾的协同作用使得 C-F 和 N-H 键在室温下发生交叉偶联反应，有效地避免了与热诱导 S2 或 S1 胺化相关的高能垒。这种转化的显著优势在于硅基硼酸酯选择性地活化有机氟化物的 C-F 键，而不会影响潜在可断裂的 C-O、C-Cl、杂芳基 C-H 或 C-N 键和 CF 基团。使用电子和空间位阻变化的有机氟化物和 N-烷基苯胺或仲胺，可一步高效合成具有芳香族、杂芳族和/或脂肪族基团的叔胺。该方案还扩展到了候选药物的后期合成，包括它们的氘代类似物。
