Organocatalytic Asymmetric Synthesis of trans‐1,3‐Disubstituted Tetrahydroisoquinolines via a Reductive Amination/Aza‐Michael Sequence

Abstract

Benzothiazoline better than Hantzsch: A stereoselective Brønsted acid catalyzed reductive amination/aza‐Michael approach towards the important class of tetrahydroisoquinolines is presented (see scheme). A biphenyl‐substituted benzothiazoline is used as the reducing agent and leads to superior yields and enantiomeric excesses compared with the frequently used Hantzsch ester. The cyclization of the amine intermediate occurs smoothly with potassium tert‐butoxide as the base and affords the trans‐1,3‐disubstituted tetrahydroisoquinolines.

Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation: Facile Synthetic Access to Highly Optically Active Trifluoromethylated Amines

“…Interestingly, employing the commonly used transfer hydrogenation agent, the Hantzsch ester ( 9 ), under the same reaction conditions resulted in only a trace amount of 7 a (4 %) with diminished enantioselectivity (45 % ee ; Scheme ). This result clearly points to the distinct differences in the reactivity between 6 d and 9 , and shows that an appropriate choice of hydride source is crucial for the outcome of this transformation 13…”

Enantioselective Synthesis of β‐Aminotetralins via Chiral Phosphoric Acid‐catalyzed Reductive Amination of β‐Tetralones

“…Recently, our group has initiated a program for the enantioselective synthesis of chiral β‐arylamines via chiral phosphoric acid‐catalyzed reductive amination of benzyl methyl ketones ,,. As a continuing effort to develop protocols to access chiral β‐arylamines via chiral phosphoric acid‐catalyzed asymmetric reductive amination, we further attempted to develop a protocol for the synthesis of chiral cyclic β‐arylamines by reductive amination of benzofused cyclic β‐ketones.…”

Advances and Applications in Organocatalytic Asymmetric aza‐Michael Addition

“…This domino strategy consisting of a reductive amination/aza-Michael addition sequence was successfully applied by Enders [27] Using a chiral phosphoric acid 83 as an organocatalyst and a biphenyl-substituted benzothiazoline 84 as hydride source, they reacted p-anisidine with keto enoate 82 to yield the reductive amination products. They then performed the intramolecular aza-Michael addition to reach trans-1,3-disubstituted tetrahydroisoquinolines.…”