Kane D Lucas, Figula Bryan C, Balaraman Kaluvu, Bertke Jeffery A, Wolf Christian
Georgetown University, Chemistry Department, Washington, D.C. 20057, United States.
J Am Chem Soc. 2025 Feb 19;147(7):5764-5774. doi: 10.1021/jacs.4c13956. Epub 2025 Feb 6.
The unique properties of fluorinated organic compounds have received intense interest and have conquered a myriad of applications in the chemical and pharmaceutical sciences. Today, an impressive range of alkyl fluorides are commercially available, and there are many practical methods to make them exist. However, the unmatched stability and inertness of the C-F bond have largely limited its synthetic value, which is very different from the widely accepted utility of alkyl chlorides, bromides, and iodides that serve everyday as "workhorse" building blocks in countless carbon-carbon bond forming reactions. This study demonstrates practical and high-yielding functionalization of the C-F bond under mild conditions, i.e., at temperatures as low as -78 °C, in short reaction times and with unconventional chemoselectivity. Cryogenic Csp-F bond cleavage using fluorophilic organoaluminum compounds together with fast nucleophile transfer of intermediate ate complexes forge carbon-carbon bonds with unactivated primary, secondary, and tertiary alkyl fluorides alike. This method, which exploits the stability of the Al-F bond as the thermodynamic driving force, is highly selective toward Csp-F bond functionalization, whereas many other functional groups including alkyl chloride, bromide, iodide, aryl halide, alkenyl, alkynyl, difluoroalkyl, trifluoromethyl, ether, ester, hydroxyl, acetal, heteroaryl, nitrile, nitro, and amide groups are tolerated, which is an unexpected reversal of long-standing main group organometallic and alkyl halide cross-coupling reactivity and compatibility patterns. As a result, the strongest single bond in organic chemistry can now be selectively targeted in high-yielding arylation, alkylation, alkenylation, and alkynylation reactions and used in late-stage functionalization applications that are complementary to currently available methods.
含氟有机化合物的独特性质引起了广泛关注，并在化学和制药科学领域有众多应用。如今，大量的烷基氟化物已商业化可得，且有许多实用方法可制备它们。然而，C-F键无与伦比的稳定性和惰性在很大程度上限制了其合成价值，这与烷基氯、溴和碘化物被广泛接受的用途截然不同，后三者在无数碳-碳键形成反应中日常都作为“主力军”构建单元。本研究展示了在温和条件下，即低至-78°C的温度、短反应时间且具有非常规化学选择性的情况下，C-F键的实用且高产率官能化。使用亲氟有机铝化合物进行低温Csp-F键裂解，同时中间体铝酸配合物进行快速亲核转移，可与未活化的伯、仲和叔烷基氟化物形成碳-碳键。该方法利用Al-F键的稳定性作为热力学驱动力，对Csp-F键官能化具有高度选择性，而许多其他官能团，包括烷基氯、溴、碘、芳基卤化物、烯基、炔基、二氟烷基、三氟甲基、醚、酯、羟基、缩醛、杂芳基、腈、硝基和酰胺基均可耐受，这与长期以来主族有机金属和烷基卤化物交叉偶联反应性及兼容性模式出现了意想不到的反转。因此，有机化学中最强的单键现在可以在高产率的芳基化、烷基化、烯基化和炔基化反应中被选择性地靶向，并用于与现有方法互补的后期官能化应用中。
