Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines (“1,8-THNs”), in addition to their regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular S_NAr N-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C–N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist PF-07258669.

螺环四氢萘啶 (THN) 是药物发现活动的宝贵支架，但由于缺乏模块化和可扩展的合成方法，进入这个 3D 化学空间受到阻碍。我们在此报告了 α-烷基化和螺环 1,2,3,4-四氢-1,8-萘啶（“1,8-THN”）及其区域异构体 1,6-THN 的自动连续流动合成来自丰富的伯胺原料的类似物。基于卤代乙烯基吡啶的光氧化还原催化氢氨烷基化 (HAA) 的环形断开方法与分子内 S _N Ar N -芳基化相结合进行测序。为了获得剩余的 1,7- 和 1,5-THN 异构体，光氧化还原催化的 HAA 步骤与钯催化的 C-N 键形成叠合。总而言之，这提供了使用相同的键断开从一组常见的未受保护的伯胺起始材料中获得四个异构 THN 核心的高度模块化途径。辉瑞 MC4R 拮抗剂 PF-07258669 螺环 THN 核心的简明合成说明了该方法的简化能力。