Enantioselective Synthesis of Benzofuran-Fused N-Heterocycles via Chiral Squaramide Catalyzed [4 + 2] Cyclization of Azadienes with Azlactones

Abstract

An asymmetric cyclization reaction of azadienes and azlactones was investigated by employing a Cinchona squaramide catalyst, which could afford a series of benzofuran-fused six-membered heterocycles containing a α,α-disubstituted amino acid unit in a highly diastereoselective (>20:1 dr) and enantioselective (up to 99% ee) manner with good to excellent yields (up to 92%). A plausible pathway was proposed to explain the reaction process.

Recent Advances in Azlactone Transformations

“…r . and 99 % ee ) (Scheme A) . The authors were able to produce almost a gram (890 mg) of the desired product in similar yields and enantiomeric excesses.…”

“…[33] Different substrates bearing diverse electronic and steric substituents in both azlactone and orthohydroxy benzhydryl alcohol moieties were well tolerated in the optimized reaction conditions and afforded the desired products with up to 98 % yield, > 95:5 d.r. For example, products bearing trifluoroacetyl (41), trimethylsilyl moieties (42) and even sterically congested polycyclic dihydrocoumarins (43) were achieved in good yields and excellent enantiomeric excesses. For example, products bearing trifluoroacetyl (41), trimethylsilyl moieties (42) and even sterically congested polycyclic dihydrocoumarins (43) were achieved in good yields and excellent enantiomeric excesses.…”

“…[42] Moreover, it is worth to mention that all products were attained with > 20:1 d.r. [43] The authors were able to produce Scheme 21. Next, control This research group also employed the same squaramidecinchona organocatalyst in the asymmetric [4+2] cycloadditions between azlactones (84) and azadienes (83), affording benzofuran-fused N-heterocycles (85) in low to excellent yields (up to 92 %) and excellent stereoselectivities (up to > 20:1 d.r.…”

Recent Advances in the Cycloaddition Reactions of 2‐Benzylidene‐1‐benzofuran‐3‐ones, and Their Sulfur, Nitrogen and Methylene Analogues

“…In 2019, Huang's group used azadiene 41 and azlactone 85 to generate benzofuranfused N-heterocycles through chiral squaramide Cat-20 catalyzed [4 + 2] cycloaddition reactions in chlorobenzene with an excellent yield and high ee and dr values (Scheme 14c). [63] The first step is a Michael addition reaction, followed by intramolecular N-acylation of enamine and opening of the oxazolone ring. Furthermore, the Michael addition step is the stereocontrol step (TS-84).…”

Chiral Brønsted Acid‐Catalyzed Asymmetric 1,4‐Addition of Benzofuran‐Derived Azadienes with 3‐Substituted indoles

“…[3] Particularly, chemists have developed a variety of catalytic asymmetric transformations of benzofuran-derived azadienes, which have provided an easy access to enantioenriched benzofuran derivatives (Scheme 1). [4][5][6][7][8][9][10] As summarized in Scheme 1a, benzofuranderived azadienes are widely utilized as four-atom building blocks in catalytic asymmetric (4 + n) cyclizations including (4 + 1), [4] (4 + 2), [3,5] (4 + 3), [6] (4 + 4), [7] (4 + 5), [8] (4 + 6) [9] cyclizations under the catalysis of chiral organocatalysts such as chiral base, N-heterocyclic carbene, bifunctional squaramide, phosphines or Pd/chiral ligands, which constructed benzofuran-fused fivemembered to ten-membered heterocyclic frameworks in an enantioselective manner. However, in contrast to rapidly developed (4 + n) cyclizations, the catalytic asymmetric 1,4addition reactions of benzofuran-derived azadienes are underdeveloped (Scheme 1b).…”