Synthesis of Substituted β‐Functionalised Styrenes by Microwave‐Assisted Olefin Cross‐Metathesis and Scalable Synthesis of Apremilast

Abstract

Preparation of diversely substituted β-functionalised styrenes by microwave-assisted olefin cross-metathesis (CM) is described. This method can be also employed in the synthesis of βdeuterated α,β-unsaturated sulfones from inexpensive allylbenzenes, though unprecedented one-pot isomerisation/deutera-tion/cross-metathesis sequence. One of such obtained CM products has been utilised in a new scalable synthesis of Apremilast (6), a potent and orally active phosphodiesterase 4 and tumour necrosis factor-α inhibitor. The same strategy was used in synthesis of an optical antipode of 6, ent-Apremilast. Scheme 1. a) Reported cross-metathesis of reactive terminal alkenes with vinyl sulfones; b) Exemplary applications of the above transformation in total synthesis; c) Envisioned CM of functionalised styrenes with vinyl sulfones. FG = distant functional group; API = Active Pharmaceutical Ingredient.

Nitro and Other Electron Withdrawing Group Activated Ruthenium Catalysts for Olefin Metathesis Reactions

“…TheZ han-1B catalyst was the least productive,w hile the nitro and the Mauduit catalysts were superior, with an impressive 81 %y ield of 39 obtained with the Umicore M71 SIMes complex. [91] There are more examples of cross-metathesis that are worth discussing, [74][75][76][77][93][94][95][96] but the limited space of this Review does not allow this.…”

“…There are more examples of cross‐metathesis that are worth discussing, [74–77, 93–96] but the limited space of this Review does not allow this.…”

Durch Nitro‐ und andere elektronenziehende Gruppen aktivierte Ruthenium‐Katalysatoren für die Olefinmetathese

“…Weitere erwähnenswerte CM‐Beispiele [74–77,93–96] können aufgrund der begrenzten Länge dieses Aufsatzes nicht diskutiert werden.…”

“…Der Zhan-1B-Katalysator wies dabei die geringste Produktivitätauf,wohingegen Ru12 und Mauduits Katalysator,m it einer eindrucksvollen Ausbeute für 39 von 81 %d urch den Umicore-M71-SIMes-Komplex, überragten. [91] Weitere erwähnenswerte CM-Beispiele [74][75][76][77][93][94][95][96] kçnnen aufgrund der begrenzten Länge dieses Aufsatzes nicht diskutiert werden.…”

Preparation of Functionalized α,β-Unsaturated Sulfonamides via Olefin Cross-Metathesis

“…It is striking that despite so many functional groups ( Scheme 1 ) having already been tested in CM, the applicability of vinyl sulfonamides as partners in this transformation is barely known 13 (although there are single examples of use in RCM - ring-closing metathesis), 14 and only one report describing CM of allyl sulfonamides 15 is available.…”