Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Cascade Reaction To Access Cyclopentane-Fused Heterocycles: Expansion of Pd−TMM Cycloaddition Donguk Ko,† Seung-yeol Baek,‡ Jae Yul Shim,† Ju Young Lee,† Mu-Hyun Baik,*,‡ and Eun Jeong Yoo*,† †
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Department of Applied Chemistry and Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea ‡ Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) and Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea S Supporting Information *
ABSTRACT: A palladium-catalyzed reaction of N-aromatic zwitterion and trimethylenemethane that gives fused Nheterocycles via dearomative [3 + 2] cycloaddition and intramolecular cyclization is developed, and a cyclopentanefused cyclic product is generated. Combining computational and experimental studies, the site-selective dearomatization and the mechanism of this novel reaction are investigated in detail, and the value of pyridinium zwitterion as a reactant is demonstrated. Scheme 1. Palladium-Catalyzed [3 + n] Cycloadditions of Trimethylenemethane
C
atalytic cycloadditions constitute an important class of organic reactions giving access to complex cyclic compounds, which play a key role in natural products, pharmaceutical agents, and functional materials.1 Compared to concerted Huisgen [3 + 2] cycloadditions,2 stepwise 1,3dipolar cycloadditions involving metal-associated reactive intermediates provide easier control of the regio- and stereoselectivity. In particular, the Pd-catalyzed cycloadditions of trimethylenemethane (TMM), in which 2π-systems, such as activated olefins, carbonyl derivatives, and isocyanates can be employed as a reacting partner, emerged as a reliable way to generate elaborate five-membered ring scaffolds (Scheme 1, A).3 Along with stereoselectivity issues associated with cycloadditions of Pd−TMM, reactants that can undergo 1,3dipolar cycloaddition with Pd−TMM to form valuable cyclic skeletons have been extensively explored. For example, 1,3dipoles, such as azomethine imines and nitrones, have been confirmed as well-matched reaction partners of Pd−TMM to generate six-membered heterocyclic compounds (Scheme 1, B).4 Subsequently, it was reported that nitroarenes could be employed in highly efficient dearomative [3 + 2] cycloadditions of Pd−TMM, forming alicyclic compounds (Scheme 1, C).5 In particular, the phosphoramidite ligand was used to form the desired product because the dearomative process was energetically unfavorable. We have investigated the use of pyridinium zwitterion as a substrate in cycloadditions for easier access of various heterocyclic compounds.6 The aromaticity of the pyridinium backbone on the zwitterion makes the intramolecular cyclization unfavorable at room temperature. However, once the dearomatization of the pyridinium zwitterion occurs, its tethered azanide moiety participates rapidly in cyclizations to © XXXX American Chemical Society
produce stable five-membered heterocycles. Based on these observations, we reported regio-divergent cycloadditions of the pyridinium zwitterions, depending on the electronic environment of the metal-bound reaction partner.7 To investigate the use of pyridinium zwitterions as substrates in cycloadditions, Received: April 3, 2019
A
DOI: 10.1021/acs.orglett.9b01178 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters we envisioned a palladium-catalyzed cascade reaction involving the dearomative [3 + 2] cycloaddition of Pd−TMM and intramolecular cyclization (Scheme 1, D), thereby generating unprecedented cyclopentane-fused heterocyclic compounds. The pyridinium zwitterion is a highly activated aromatic compound; therefore, the use of functional groups, ligands, or high temperatures, typically necessary to force dearomatization, should be unnecessary. In addition, the obtained cyclopenta[c]pyridine derivative is an important structural motif in biologically active molecules,8 and it cannot easily be constructed through other one-pot reactions. We began our study by analyzing the DFT-calculated MOdiagrams of the pyridinium zwitterion and the Pd−TMM species (Figure 1). The LUMO of the pyridinium zwitterion,
Table 1. Optimization of the Cascade Reaction of Pyridinium Zwitterion and Pd−TMMa,b
entry
solvent
1 2 3 4 5 6 7 8 9
DME CH2Cl2 CHCl3 THF THF THF THF THF THF
HA
3a (%)
4a (%)
5a (%)
15 0 40 78 (72)c
20d 20 20 20 20 (13)c
4 27 56 96 (
