a Reaction conditions: 1a (0.10 mmol),2a (0.15 mmol), Pd2(dba)3 (5 mol%) and ligand (11 mol%) in 1.0 mL of solvent under an N2 atmosphere at 25 °C for 1 h.b Yield of 3a was determined by1H NMR spectroscopic analysis of the crude product with 1,3,5-trimethoxybenzene as an internal standard.c Pd(PPh3)4 (10 mol%).d Pd(PPh3)4 (5 mol%).e Pd(PPh3)4 (2.5 mol%).f Pd(PPh3)4 (2.0 mol%). g Isolated yield of 3a on a 0.2 mmol-scale reaction.
Under the optimal reaction conditions in hand, the substrate scope of benzofuran-derived azadienes 1 was investigated and the results were summarized in Scheme 3. Benzofuran-derived azadienes 1bearing different N -protecting groups participated in the reaction smoothly, leading to the corresponding products 3b(77% yield) and 3c (90% yield), respectively. In addition, azadienes 1 bearing various electron-withdrawing groups (fluoro, chloro, bromo, and cyano) or electron-donating (methyl and methoxy) at the para , meta or ortho position of the aryl ring were well accommodated. The target products3d -3n were delivered in 79-96% yields. It was noteworthy that 2-Cl and 2-Me-substituted substrates 1l and1m underwent the reaction smoothly, affording the target products 3l (80% yield) and 3m (79% yield), respectively, which is presumably attributed to the steric effect. Naphthyl and furanyl moieties also facilitated the formation of3o (92% yield) and 3p (90% yield), respectively. In a similar fashion, the reactions of benzofuran-derived azadienes1 bearing various substituents (bromo, methoxy, and chloro) at the C4-C7 positions of the benzofuran ring also efficiently proceeded to afford the target products 3q -3u in 83-92% yields.
Scheme 3 Substrate scope for Pd-catalyzed [4 + 4] cycloaddition of benzofuran-derived azadienes 1 and dimethyl malonate derivative 2a .
Then, the protocol generality was explored by extending the substrate scope of homo-TMM donors 2 (Scheme 4). The analog of2a , that is, substituted malononitrile 2b , exhibited a good reactivity to form the target products 3v (91% yield) and3w (75% yield), respectively. Compared to the symmetrical malonate-type substrates, the cyano-substituted ester enolate2c obviously deteriorated the reaction efficiency, leading to3x in a moderate yield (41% yield). Unfortunately, the more sterically hindered t -butyl ester counterpart 2d was used, and only a trace amount of the desired 8-membered product3y was detected. The bis(phenylsulfonyl)methane derivative2e also proved to be unreactive in the [4 + 4] cycloaddition reaction. The molecular structure of compound 3awas further confirmed by the X -ray single crystal crystallographic determination (CCDC 2235088, see the SI for details).
Scheme 4 Substrate scope for Pd-catalyzed [4 + 4] cycloaddition of benzofuran-derived azadienes 1 and dimethyl malonates derivatives 2 .
To further demonstrate the versatility and effectiveness of this catalytic system, a gram-scale reaction of compound 3a with a 2.5 mol% catalyst loading was performed, providing an acceptable yield (91% yield) (Scheme 5a). Subsequently, the 4-toluenesulfonyl (Ts) group of 3a could be removed in the presence of Mg in MeOH, yielding the corresponding benzofuro[3,2-b ]azocine 4 in 86% yield.[19]
Scheme 5 Demonstration of the synthetic utility.
Furthermore, the catalytic asymmetric [4 + 4] cycloaddition version has also been explored, and several chiral ligands were screened (see Table S1 for the details). The reaction provided moderate enantioselectivity (61% ee) with Pd2(dba)3 as the catalyst in the presence of chiral ligand L* (Scheme 6).
Scheme 6 The asymmetric [4 + 4] cycloaddition.
A mechanism was proposed to illustrate the Pd-catalyzed [4 + 4] cycloaddition (Scheme 7). First, the initial oxidative addition of a catalytically active Pd(0) species with substrate 2a and the deproton process by the tert -butoxy anion forms the key PdII-π-allyl complex intermediate A . Then, the attack by the carboanion of intermediate A to azadiene1a provides aromatization intermediate B . Subsequently, the addition of a nitrogen anion to π-allyl-palladium in aromatization intermediate B affords the eight-membered ring3 by intramolecular cyclization and regenerates the active palladium catalyst for the next catalytic cycle.
Scheme 7 Proposed mechanism.
Conclusions
In summary, we have developed an efficient Pd-catalyzed [4 + 4] cycloaddition of homo-TMM all-carbon 1,4-dipoles with benzofuran-derived azadienes, affording various benzofuro[3,2-b ]azocines in good to excellent yields (up to 96% yield) with exclusive regioselectivities. The reaction proceeded with broad substrate scope and excellent functional group tolerance. The high-order cycloaddition of homo-TMM all-carbon 1,4-dipoles provided a convenient and mild route to the synthesis of 8-membered rings. Further investigations on the asymmetric [4 + 4] cycloaddition are currently underway in our laboratory.
Experimental
Under a nitrogen atmosphere, benzofuran-derived azadienes 1 (0.2 mmol) and Pd(PPh3)4 (15.4 mg, 0.005 mmol) were added sequentially into a flame-dried Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and back-filled with nitrogen for three times. Then the anhydrous DCM (2.0 mL) was added viasyringe sequentially and the resulting mixture stirred at 25 ℃. Then, TMM precursors 2 (0.3 mmol) was added. After completion, the mixture was concentrated and purified by column chromatography (petroleum ether/ dichloromethane = 4:1) to give the corresponding cycloadducts 3 .
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
We are grateful for financial support from National Key Research and Development Program of China (2021YFA0804900), the NSFC (22171082, 21971062), the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (No. 2022R01007), and Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism.
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