Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA.
Molecules. 2022 Jun 27;27(13):4123. doi: 10.3390/molecules27134123.
The Friedländer synthesis offers efficient access to substituted quinolines from 2-aminobenzaldehydes and activated ketones in the presence of a base. The disadvantage of this procedure lies in the fact that relatively few 2-aminobenzaldehyde derivatives are readily available. To overcome this problem, we report a modification of this process involving the in situ reduction of 2-nitrobenzaldehydes with Fe/AcOH in the presence of active methylene compounds (AMCs) to produce substituted quinolines in high yields. The conditions are mild enough to tolerate a wide range of functionality in both reacting partners and promote reactions not only with phenyl and benzyl ketones, but also with β-keto-esters, β-keto-nitriles, β-keto-sulfones and β-diketones. The reaction of 2-nitroaromatic ketones with unsymmetrical AMCs is less reliable, giving a competitive formation of substituted quinolin-2(1)-ones from the cyclization of the Knoevenagel intermediate which appears to be favored when certain large groups are adjacent to the AMC ketone carbonyl.
弗里德尔兰德合成法提供了一种有效的方法，可在碱的存在下，由 2-氨基苯甲醛和活化酮合成取代的喹啉。该方法的缺点在于相对较少的 2-氨基苯甲醛衍生物易于获得。为了克服这个问题，我们报告了对该过程的修改，涉及在活性亚甲基化合物（AMCs）存在下用 Fe/AcOH 将 2-硝基苯甲醛原位还原，以高产率生成取代的喹啉。反应条件温和，可耐受反应物中广泛的官能团，并不仅促进与苯基和苄基酮的反应，还促进与β-酮酯、β-酮腈、β-酮砜和β-二酮的反应。2-硝基芳酮与不对称 AMC 的反应不太可靠，由于 Knoevenagel 中间体的环化作用，生成取代的喹啉-2(1)-酮的竞争形成，当某些大基团与 AMC 酮羰基相邻时，这种环化作用似乎更有利。
