Chiral Bromonium Salt (Hypervalent Bromine(III)) with N-Nitrosamine as a Halogen-Bonding Bifunctional Catalyst

Abstract

There has been a great focus on halogen-bonding as a unique interaction between electron-deficient halogen atoms with Lewis basic moieties. Although the application of halogen-bonded atoms in organic chemistry has been eagerly researched in these decades, the development of chiral molecules with halogen-bonding functionalities and their utilization in asymmetric catalysis are still in the\ir infancy. We have previously developed chiral halonium salts with amide functionalities, which behaved as excellent catalysts albeit in only two reactions due to the lack of substrate activation abilities. In this manuscript, we have developed chiral halonium salts with an N-nitrosamine moiety and applied them to the Mannich reaction of isatin-derived ketimines with malonic esters. The study focused on our novel bromonium salt catalyst which provided the corresponding products in high yields with up to 80% ee. DFT calculations of the chiral catalyst structure suggested that the high asymmetric induction abilities of this catalyst are due to the Lewis basic role of the N-nitrosamine part. To the best of our knowledge, this is the first catalytic application of N-nitrosamines.

Keywords: N-nitrosamine; asymmetric catalysis; bromonium salt; halogen bonding; hypervalent bromine.

Figure 1

Examples of chiral halogen-bonding catalysts.

Scheme 1

Synthesis of chiral halonium salts with N-nitrosamine moiety.

Scheme 2

Screening of the chiral halonium salt catalysts.

Figure 2

Substrate scopes. Isolated product yields are shown.

Figure 3

Structure of 4a and 8.

Figure 4

¹H NMR charts (in CDCl₃) of 4a with different equivalents of 5a (left), and 6a (right).

Figure 5

¹H NMR titration experiments (in CDCl₃) of 4a with 5a (left), and 6a (right). The spots show the chemical shift differences from additive-free values at various equivalent of additives. Blue spot means the chemical shifts differences for H1, and the orange spot means that of H4 (Figure 4). The binding constants K were calculated by Bindfit.

Figure 6

Conversions of 5a in an optimal condition (Table 1, Entry 1) with different catalyst (black: without catalyst, blue: with 4a (2.5 mol%), orange: with 8 (2.5 mol%)) monitored by ¹H NMR.

Figure 7

Plausible reaction mechanism (left), the DFT-calculated optimized structure of 4a (M06-2X/6-31G(d)) generated by GaussView 6 (right, upper), and the plausible transition state structure (right, lower). The Br···O distance of the calculated structure is 3.11 Å.