Pd‐Catalyzed Orthogonal Knoevenagel/Perkin Condensation–Decarboxylation–Heck/Suzuki Sequences: Tandem Transformations of Benzaldehydes into Hydroxy‐Functionalized Antidiabetic Stilbene–Cinnamoyl Hybrids and Asymmetric Distyrylbenzenes

Abstract

Tandem reactions that involve chemoselective Knoevenagel/Perkin condensation-decarboxylation-Heck/Suzuki coupling or Heck-aldol sequences have been achieved. This enabled the first concise and efficient synthesis of several important hydroxy-functionalized compound classes, such as stilbene-cinnamoyl hybrids (potent protein tyrosine phosphatase1B inhibitors), cinnamoyl-cinnamic acid hybrids, asymmetric distyrylbenzenes, and biarylstyrenes. Previously reported synthesis require multiple steps and protection/deprotection manipulations.

Tandem Heck/Decarboxylation/Heck Strategy: Protecting‐Group‐Free Synthesis of Symmetric and Unsymmetric Hydroxylated Stilbenoids

“…However, one of the coupling partners, that is, styrene, is inevitably prone to polymerization, difficult to synthesize, and tricky to purify. To counteract this problem, generation of styrene5 in situ (by Knoevenagel decarboxylation,5a–c Hunsdiecker,5d Wittig–Horner,5e dehydrohalogenation Heck5f reaction) and subsequent tandem coupling with an arylhalide to yield stilbenoids have come to the forefront. In contrast, the synthetic efficiency for hydroxy6 functionalized stilbenoids is hampered by the involvement of additional protection/deprotection strategies 6b…”

“…Mechanistically, it is presumed that 4‐halophenol reacts with acrylic acid to form 4‐hydroxy cinnamic acid (first Heck coupling; Scheme ) which undergoes decarboxylation according to the quinomethide5a mechanism to form 4‐hydroxystyrene in situ. The second Heck coupling proceeds with another 4‐halophenol to form the symmetric hydroxylated stilbenoid.…”

Glycerol as Suitable Solvent for the Synthesis of Metallic Species and Catalysis

“…Shina and co‐workers obtained hydroxy‐biarylstyrenes by a one‐pot sequential Suzuki cross‐coupling/Knoevenagel condensation–decarboxylation reaction in glycerol (40–49 % yields), improving the reactivity in relation to the process carried out in DMF (10 % yield) or PEG (15 % yield) (Scheme ) 36…”

Pd‐ and Cu‐Catalyzed Stereo‐ and Regiocontrolled Decarboxylative/CH Fluoroalkenylation of Heteroarenes

“…At this stage, we investigated the ability of the protodecarboxylative fluoroalkene product 4 to react with 1 a through a conventional Fujiwara-Moritani oxidative Heck-type coupling (Scheme 3). [21] To that purpose, the alkene 4 was generated from a-fluoroacrylic acid 2 A [22] and then either (a) allowed to react with 1 a [Scheme 3, Equation (1)] or (b) isolated beforehand and subsequently subjected to an oxidative Hecktype reaction [Scheme 3, Equation (2)]. Both scenarios failed, precluding a two-step mechanism initially involving a protodecarboxylation followed by a Fujiwara-Moritani oxidative Hecktype coupling.…”