Background and Originality Content
The eight-membered azacycles are widely presented in various natural products and bioactive pharmaceuticals.[1-6] Due to their significant importance, concise and efficient synthetic methods are in high demand for the synthesis of eight-membered azacycles.[7] In recent years, the creation of eight-membered ring systems has been facilitated easily by the implementation of transition-metal-catalyzed high-order cycloadditions,[8] which has attracted much attention.
Scheme 1 Palladium-catalyzed cycloadditions of TMM 1,n -dipole precursors.
Trimethylenemethane (TMM) is an effective dipole with a wide range of applications that allows for the synthesis of highly functionalized cyclic compounds.[9] To date, an assortment of TMM dipole precursors has been developed to enable the efficient construction of cyclic compounds (Scheme 1a), encompassing methylene cyclopropanes,[10] 2-substituted allyl carbonates (Trost-TMM),[9h,11,12]γ -methylidene-δ -valerolactones,[8g,13]2-methylidenetrimethylene carbonates,[14]pyrrolidines,[15]2-methylene-1-indanols.[16] Among various types of TMM dipole precursors, Trost-TMM is the most extensively investigated one, which served as an efficient three-carbon unit in Pd-catalyzed [3+n] cycloadditions.[9h] In this field, our group successfully realized several asymmetric [3 + 4] cycloadditions of Trost-TMM precursors with different 4-atom synthons, furnishing a series of fused azepines or cycloheptanes with excellent regio-, diastereo- and enantioselectivities in recent years (Scheme 1b).[17] Based on the well-developed conventional Trost-TMM, in 2020, the Trost group developed a novel homo-TMM all-carbon 1,4-dipole precursor, which realized a Pd-catalyzed [4 + 2] cycloaddition to afford chiral cyclohexanes or spiro heptanes (Scheme 1c).[18] However, the transition-metal-catalyzed high-order cycloaddition of this novel homo-TMM all-carbon 1,4-dipole precursor for the synthesis of medium-sized rings has yet to be investigated.
Scheme 2 Design of the Pd-catalyzed [4 + 4] cycloaddition of homo-TMM all-carbon 1,4-dipole precursors with benzofuran-derived azadienes.
Inspired by Trost’s work in 2020 and in conjunction with our continuing efforts in the construction of medium-sized rings, we envisaged that the homo-TMM all-carbon 1,4-dipole precursors may undergo a [4 + 4] cycloaddition with azadienes to form azocines (Scheme 2). However, the inhibition of the regioselectivity induced by the potentially rival [4 + 2] cycloaddition of imines or alkenes in azadienes presents considerable difficulty in this process. Herein, we present the Pd-catalyzed [4 + 4] cycloaddition of homo-TMM all-carbon 1,4-dipole precursors with benzofuran-derived azadienes, providing an efficient and convenient approach to access benzofuro[3,2-b ]azocines with exclusive regioselectivitives.
Results and Discussion
Initially, the reaction of benzofuran-derived azadiene 1a , derived from benzofuran, with dimethyl malonate derivative 2awas conducted to screen the reaction conditions. In the presence of 5 mol% Pd2(dba)3 as the catalyst, 11 mol% diphosphine ligand L1 or L2 in DCM for 1 h, no desired target product 3a was detected (Table 1, entries 1 and 2). Subsequently, the screening of preliminary monophosphine ligands showed that ligand L3 turned out to be a suitable ligand, providing 3a in 91% yield with exclusive regioselectivity (Table 1, entries 3-5). It is noteworthy that using Pd(PPh3)4 instead of the combination of Pd2(dba)3 with ligand L3further enhanced the reaction efficiency, affording 3a in 95% yield (Table 1, entry 6). A series of commercial solvents, including DCE, THF, and toluene, were used in the [4 + 4] cycloaddition reaction, but none of them afforded better results than DCM (Table 1, entries 7-9). Lowering the catalyst loading from 10 mol% to 2.5 mol% did not affect the reaction efficiency, and achieved optimal reaction outcomes in terms of yield (95% NMR yield and 95% isolated yield) (Table 1, entries 10-12).
Table 1 Optimization of reaction conditions of the reaction.a