A Simple Approach to Unsymmetric Atropoisomeric Bipyridine N,N′‐Dioxides and Their Application in Enantioselective Allylation of Aldehydes

Abstract

The [2 + 2 + 2] cyclotrimerization of 1-isoquinolinyl-1,7-octadiyne with benzonitrile catalyzed by CpCo(CO) 2 opened a new pathway for a synthesis of unsymmetrical axially chiral bipyridine N,N'-dioxides. The N,N'-dioxide 3a was found to be highly catalytically active and enantioselective for the asymmetric allylation of aldehydes with allyltrichlorosilane. The allylation took place with even 1 % of the catalyst with an enantioselectivity up to 87 % ee.Keywords: allylation; asymmetric catalysis; Lewis bases; microwave heating; organic catalysis Recently, asymmetric organocatalysis based either on Lewis acid or base interactions has been recognized as an efficient method for obtaining chiral compounds with high enantioselectivity.[1] Among the numerous examples of such molecules considerable attention has been attracted by amine N-oxides as powerful electron-pair donors. In this context, pyridine Noxides and bipyridine N,N'-dioxides are of special interest in cases where the pyridine moiety is a part of a chiral scaffold. The electron-donating properties of pyridine N-oxides make them rather strong Lewis bases that are able to activate a number of reactants for a plethora of reactions such as allylation and alkylation of carbonyl compounds, conjugated addition, aldol reaction, desymmetrization of epoxides, epoxidation, etc.[2] Although a number of various pyridine-, [3][4][5][6][7][8] bipyridine-, [9][10][11] and terpyridine-based ligands [12] has been introduced into organic synthesis, there is a considerable synthetic demand for the development of new bipyridine-based organocatalysts.In this regard it would be attractive to develop a methodology that would allow the simple and fast synthesis of bipyridine N,N'-dioxides bearing various substituents in a close vicinity to the chiral scaffold. Recently, we have reported that the cobalt-catalyzed [2 + 2 + 2] cyclotrimerization of diynes with nitriles is a suitable method for the preparation of potential pyridine-based organocatalysts with axial chirality. Unfortunately, the catalytic activity and enantioselectivity of the corresponding chiral pyridine Noxides was low: catalysis of the reaction of allyltrichlorosilane or diethylzinc with benzaldehyde afforded after 3 days at 20 8C the corresponding products in 50 % (20 % ee) and 72 % (17 % ee), respectively. [13] In the course of this cyclotrimerization research project aiming at the preparation of various heterocycles, we realized that [2 + 2 + 2] cyclotrimerization could be used for a modular synthesis of potentially atropoisomeric bipyridines from suitably substituted a-heteroaryl-a,w-diynes and nitriles (Scheme 1). [14] In this context, a plethora of unsymmetrically substituted bipyridines could be prepared by varying the substituents R 1 and R 2 in the reactants. Such bipyridines would constitute an ideal starting material for the preparation of chiral bipyridine N,N'-dioxides, because they could, besides having axial chirality, also exert additional steric and electronic effects caused by the unsymmet...

Synthesis, copper(II) complexes and catalytic activity of substituted 6-(1,3-oxazolin-2-yl)pyridine-2-carboxylates

“…Moreover in all the non-coordinating solvents the predominant enantiomer of the product had opposite configuration (as also observed in Ref. [38][39][40][41][42]) as compared with O-coordinating solvents. Dichloromethane was found to be the most appropriate solvent: the absolute values of enantiomeric excess reached 37% ee.…”

One‐Pot Trimetallic Relay Catalysis: A Unified Approach for the Synthesis of β‐Carbolines and Other [c]‐Fused Pyridines

“…Benzofuro-and benzothienopyridines are the primary molecular architectures of many biologically active compounds and drug candidates, [22] and find application in materials science as well. [23] Theversatility of this method was furthered by setting up new approaches to isoquinolines (product 21 a), 2-(isoquinolin-1-yl)quinolones (product 21 b), [24] and 4-hydroxyisoquinolines (product 21 c), which otherwise require multistep synthesis.Isoquinolines are the key structural scaffolds of several naturally occurring alkaloids;t hey are also the principal components of numerous therapeutics and can provide the backbone for chiral ligands. [25] In conclusion, we have presented unprecedented examples of relay catalysis through the sequential use of silver, bismuth, and palladium catalysts to access an array of distinct b-carbolines.T he method was subsequently extended to the synthesis of intriguing [c]-fused pyridines,such as benzofuroand benzothieno [2,3-c]pyridines,a nd isoquinolines.I ntriguing mechanistic details governing these processes were elucidated.…”

Proton Affinities of Organocatalysts Derived from Pyridine N-oxide

“…16,17 The experiments were performed with a TSQ Classic mass spectrometer equipped with an electrospray ion source and a QOQ configuration of the manifold (Q stands for quadrupole and O for octopole). Mixing milimolar amounts of catalysts with reference bases -DIPEA (diisopropylamine), TPA (tripropylamine), TBA (tributylamine), TEA (triethylamine) and DMAN (N,N,N′,N′-Tetramethyl-1,8-naphthalenediamine) in methanol (HPLC quality) lead to the formation of mixed proton-bound complexes of the structure [A-H-B] + where A stands for the catalyst and B for the reference base.…”

“…It has been shown previously that catalysts derived from the axially chiral 2,2′-bipyridyl N,N′-dioxide or 2-aryl pyridine N-oxide are very efficient as catalysts of the reaction shown in Scheme 1 providing both high yields and high enantioselectivities. [16][17][18][19][20] By combination of an extended kinetic method and theoretical calculations we aimed at determining the gas-phase proton affinities of a series of organocatalysts employed in the allylation reaction (Chart 1) and theoretical values of their acidity constants in solution (pK a ). Recently, we have shown that molecules derived from 2,2′-bipyridyl N,N′-dioxide have very large proton affinities (1050 -1070 kJ mol -1 ) in the gas phase and can be denoted as superbases.…”