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