Continuous-Flow Stereoselective Synthesis in Microreactors: Nucleophilic Additions to Nitrostyrenes Organocatalyzed by a Chiral Bifunctional Catalyst

Abstract

Metal-free stereoselective additions of activated nucleophiles to β-nitrostyrenes were investigated under continuousflow conditions in microreactors, in the presence of a chiral bifunctional catalyst. Optimization of the experimental setup gave excellent enantioselectivities (up to 85% e.e.) and higher productivities if compared to the flask syntheses. The potential of this flow chemistry approach was demonstrated by the successful synthesis of an advanced intermediate for the preparation of the GABA B receptor agonist Baclofen.

Green Asymmetric Organocatalysis

“…Continuous‐flow conditions in microreactors were applied to the Michael addition of 9 to 2 a with bifunctional thiourea C36 as the catalyst . Microreactors significantly accelerated the reaction and Michael adduct 10 a was obtained in just 5 min; no change in yield or selectivity was observed (Table ).…”

Organocatalytic Michael Addition to (D)-Mannitol-Derived Enantiopure Nitroalkenes: A Valuable Strategy for the Synthesis of Densely Functionalized Chiral Molecules

“…Considering the rising interest in the in-flow preparation of APIs [15][16][17], based on these results and with the aim to further accelerate the reaction, we explored the possibility of developing a continuous flow method for the organocatalytic Michael addition to nitroalkene 2 [18].…”

Enantioselective Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S)-Pregabalin Precursor and (S)-Warfarin

“…In our previous work [30], the addition of acetylacetone 2 to nitrostyrene 1 catalyzed by Takemoto thiourea 3 [31,32] In this work, the glass microreactor was replaced with a commercially available PEEK tubing designed for HPLC applications (PEEK microreactor II, inner diameter 0.127 mm, length 79 cm, total volume 10 μL) that was coiled in a bundle and immersed in a preheated oil bath. A Chemix Fusion 100 syringe pump equipped with two Hamilton gastight 1 mL syringes was used to feed the reagents into the microreactor through a T-junction (Syringe A: nitrostyrene 1; Syringe B: acetylacetone 2 and Takemoto thiourea 3).…”

“…On the other hand, homogeneous organocatalytic reactions performed under continuous flow conditions, for example in microreactors, are much less explored, the very few studies being almost exclusively limited to proline derivatives [26][27][28][29]. Recently, we have reported the use of a chiral bifunctional catalyst in glass microreactors, exploiting the potentiality of microfluidic technique to successfully accomplish enantioselective Michael type additions reactions [30]. Commercially available glass microreactors have extensively been used for performing continuous flow organic transformations.…”