Cu(I)-Catalyzed 6-endo-dig Cyclization of Terminal Alkynes, 2‑Bromoaryl Ketones, and Amides toward 1‑Naphthylamines: Applications and Photophysical Properties

Functional group substituted 1-naphthylamines, especially N-methylated ones, play important roles in numerous chemical and biological processes. However, these compounds’ general and step-economic syntheses are highly limited, which seriously restricts efforts to improve the properties and develop new functions for this kind of compound. In this report, we describe the development of an efficient, convenient, and general method for the synthesis of valuable functionalized 1-naphthylamines directly from readily available terminal alkynes, 2-bromoaryl ketones, and amides via Cu­(I)-catalyzed benzannulation in a green solvent (i.e., water) under Pd- and ligand-free conditions. A total of 82 functionalized 1-naphthylamines, especially synthetically and biologically useful N-methylated compounds, are synthesized in isolated yields up to 95%. Some unique features of the reaction are as follows: (1) exclusive 6-endo-dig selectivity, (2) ready incorporation of a broad range of functional groups directly from easily available substrates, and (3) amides that can be used as aminating agents and that are excellent alternatives to toxic and/or odorous amines. Due to facile tuning of functional groups for the reaction, the products possess good electronic donor–acceptor structures and exhibit intriguing photophysical properties, such as tunable and polarity-sensitive fluorescence emission and large Stokes shifts (up to 258 nm). Utilizing the products’ unique polarity-sensitive fluorescence response, we successfully applied the 1-naphthylamine derivatives, such as compound 91, to image lipid droplets (LDs) and monitor cellular LDs growth. The previously mentioned advantages of this methodology, along with the mild conditions, simple operation, and scalable synthesis, may allow this novel reaction to be extended to varied applications in chemistry, biology, and materials science.

官能团取代的1-萘胺（functional group substituted 1-naphthylamines），尤其是N-甲基化衍生物，在众多化学与生物过程中发挥关键作用。然而，此类化合物的通用且兼具步骤经济性的合成方法却极为匮乏，这严重制约了对其性能优化与新功能开发的研究进程。本研究报道了一种高效、便捷且通用的合成策略：以易得的端炔、2-溴芳基酮与酰胺为原料，在无钯、无配体的条件下，以绿色溶剂（即水）为反应介质，通过一价铜（Cu(I)）催化的苯环化反应，直接合成具有高应用价值的官能团化1-萘胺。本研究共合成82种官能团化1-萘胺，其中包括合成与生物应用价值突出的N-甲基化衍生物，分离产率最高可达95%。该反应具有如下独特特性：(1) 专一的6-endo-dig环化选择性；(2) 可直接从易得底物中引入广泛的官能团；(3) 酰胺可作为氨化试剂，是有毒/恶臭胺类的优良替代试剂。由于反应中官能团可便捷调控，所得产物具备优良的电子给体-受体结构，并展现出引人关注的光物理性能，例如可调谐且对极性敏感的荧光发射，以及大斯托克斯位移（Stokes shifts，最大可达258 nm）。利用产物独特的极性敏感荧光响应特性，本研究成功将1-萘胺衍生物（如化合物91）应用于脂滴（lipid droplets, LDs）成像，并实现了细胞内脂滴生长的实时监测。本方法兼具上述优势，且反应条件温和、操作简便、可规模化合成，有望将这一新型反应推广至化学、生物学与材料科学等多个领域的多样化应用中。