Enantio‐ and Diastereoselective Nucleophilic Addition of N‐tert‐Butylhydrazones to Isoquinolinium Ions through Anion‐Binding Catalysis

Abstract

A highly enantio-and diastereoselective thioureacatalyzed dearomatization of isoquinolines employing N-tertbutylhydrazones as neutral a-azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and highyielding transformations provide appealing dihydroisoquinoline derivatives. Scheme 1. Dearomatization of azaarenes.

Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts

“…This reaction, which leads to the dearomatization of the isoquinoline, proceeded in a highly enantioselective manner in the presence of bifunctional thiourea-based catalyst C41. Two chiral centers were formed in the reaction, and the diastereoselectivity was >20:1 in all cases studied [98]. If the reaction proceeds by anion-binding catalysis, it is expected that the geometry, size and coordination ability of the counteranion should have a marked effect on the results.…”

N,N‐Dialkylhydrazones as Versatile Umpolung Reagents in Enantioselective Anion‐Binding Catalysis

“…However, despite the versatility of these compounds exhibiting umpolung reactivity as nucleophilic reagents, until now only two different activation modes in organocatalysis, H‐bonding [4] and chiral counteranion catalysis [14] (Figure 1 b), have been efficiently employed [15] . In fact, the use of hydrazones as nucleophiles through an anion‐binding activation approach has only been recently envisioned [16] . Hence, we herein report on the first use of DAHs as suitable nucleophiles for anion‐binding catalysis by embracing an anion‐bridging strategy to allow for the facile and direct access to enantiomerically enriched adducts (Figure 1 c).…”

Halides as versatile anions in asymmetric anion-binding organocatalysis

“…It is worthy to be mentioned, that Reissert dearomatizations of N -heteroarenes, especially of isoquinolines [ 36 ], and nucleophilic addition to 1-chloroisochromanes [ 38 ] have become benchmark reactions in the context of anion-binding catalysis. Besides reports of thiourea-catalyzed reactions with different nucleophiles [ 39 – 40 ], the focus has also been turned to the development of other catalyst systems that are not based on N–H bonds, such as the chiral silanediol catalysts first reported by Mattson and co-workers in 2013 [ 19 – 20 ]. Furthermore, it is worthy to mention that in parallel to the investigations towards new chiral catalysts and asymmetric methodologies, a few innovative nonchiral alternative H-donor or halide-binding organocatalysts, like, e.g., tridentate phosphoramides [ 41 ], onium salts [ 42 ] such as Berkessel's pyridinium systems [ 43 ], or Huber's bis-iodo imidazolium [ 44 ] and neutral bridged 2,6-diiodo‐3,4,5-trifluorophenyl-type catalysts [ 45 ].…”