Letter Cite This: Org. Lett. 2018, 20, 5457−5460
pubs.acs.org/OrgLett
Biomimetic Oxidative Coupling Cyclization Enabling Rapid Construction of Isochromanoindolenines Jinxiang Ye,† Yuqi Lin,† Qing Liu, Dekang Xu, Fan Wu, Bin Liu, Yu Gao, and Haijun Chen* College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China
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S Supporting Information *
ABSTRACT: Herein, we report a biomimetic oxidative coupling cyclization strategy for the highly efficient functionalization of tetrahydrocarbolines (THCs). This process enables rapid access to complex isochromanoindolenine scaffolds in moderate to excellent yields. The reaction proceeds smoothly and rapidly (complete within minutes) in an open flask. This operationally simple protocol is scalable and compatible with a wide range of functional groups. Late-stage functionalization of a pharmacologically relevant molecule is also demonstrated.
T
he development of concise and efficient approaches for the rapid construction of diverse intricate molecular architectures is of crucial importance. Therefore, this endeavor still remains a preeminent goal in current synthetic methodology.1 Oxidative coupling reactions enable the direct formation of new bonds in a sustainable and efficient manner2 and are extensively applied to synthesize complex molecules.3 Tetrahydrocarbolines (THCs) are a commonly occurring core motif in several ubiquitous biologically active natural alkaloids and pharmaceuticals.4 Among THCs, tetrahydro-βcarbolines (THβCs) and tetrahydro-γ-carbolines (THγCs) possess interesting pharmacological profiles,4a,5 indicating that they are promising building blocks for the rapid synthesis of complex scaffolds in drug discovery and development.4b,6 Therefore, functionalization of THCs has become an intense subject in chemical research.7 For example, Liu et al. reported a practical metal-free oxidative C−H functionalization of Ncarbamoyl THCs in the α-position.8 Kozmin and co-workers demonstrated an efficient synthetic strategy to a skeletally diverse chemical library of indoloquinolizidines.9 Roussi et al. reported a direct functionalization of THβCs at the C4 position with various nucleophiles.10 We recently reported a new oxidative rearrangement coupling reaction for the synthesis of pyrrolo[3,4-b]quinolin-9-amines via efficient functionalization of THβCs.11 Isochromanoindolenines are the central core of some natural products such as voacalgine A and bipleiophylline (Figure 1a).12 However, the synthesis of isochromanoindolenine scaffold had been scarcely explored before. Recently, Vincent et al. developed an oxidative coupling strategy to access isochromanoindolenines by using excess silver oxide as the oxidant (Figure 1b).12c,13 In a continuing effort on late-stage functionalization of complex molecules,14 we hypothesized that direct functionalization of THCs for the synthesis of isochromanoindolenines could be achieved via a catalytic synthesis process.15 Herein, we present the oxidative coupling between THCs and 2,3-bishydroxybenzoic acid using iron(II) phthalocyanine (FePc) as a catalyst via biomimetic catalytic © 2018 American Chemical Society
Figure 1. Recent work for the construction of isochromanoindolenine scaffolds.
oxidation reaction (Figure 1c),16 allowing for rapid access to a library of isochromanoindolenines in a highly efficient and selective manner. We began our investigation by using THβC as the substrate. After considerable efforts, the optimized reaction conditions were found to furnish the desired product efficiently (Table 1). FePc was crucial for the conversion (entry 1, Figures S1 and S2),17 and other transition-metal catalysts did not lead to the expected conversion (entry 2, Table S1).17 Using hydrogen peroxide in lieu of TBHP (tert-butyl hydroperoxide) did not afford the desired product (entry 3). Replacing CH3CN with other solvents gave the desired product in low to modest yield (entry 4, Table S2),17 while dichloromethane as the solvent gave a similar yield. Accumulating evidence has suggested that acetic acid can accelerate some catalytic oxidation reactions.18 Received: July 27, 2018 Published: August 23, 2018 5457
DOI: 10.1021/acs.orglett.8b02377 Org. Lett. 2018, 20, 5457−5460
Letter
Organic Letters Table 1. Optimized Reaction Conditionsa
entry
variation of reaction conditions
yield (%)b
1 2d 3 4d 5 6 7d
as shown other catalyst instead of FePc H2O2 instead of t-BuOOH other solvents without AcOH without MsOH other acids instead of MsOH
85 (82)c
