Non‐Biaryl Atropisomers in Organocatalysis

Abstract

A new class of 6'-hydroxy cinchona alkaloids, with a non-biaryl atropisomeric functionalisation at position 5' of the quinoline core can be prepared by an easy amination procedure. These are the first derivatives for which the principle of atropisomerism is engrafted in the classical core of the cinchona alkaloids. The aminated cinchona alkaloids are effective organocatalysts for the Michael addition of beta-keto esters to acrolein and methyl vinyl ketone, in up to 93 % ee (ee=enantiomeric excess), as well as for the asymmetric Friedel-Crafts amination of a variety of 2-naphthols, permitting the preparation of the latter in up to 98 % ee. The aminated 8-amino-2-naphthol itself is the first chiral organocatalyst based on non-biaryl atropisomerism. The two enantiomers of this chiral primary amine can be used for the direct alpha-fluorination of alpha-branched aldehydes. The fluorinated compounds can thereby be accessed in up to 90 % ee.

Recent Advances in Catalytic Enantioselective Fluorination Reactions

“…[50] Since only a limited number of organocatalyzed fluorinations of abranched aldehydes had been reported at that time, [47a,b] aldehyde 62a was selected as a test substrate in combination with NFSI as a fluorine source. Organocatalyzed fluorination reactions using 61 were found to be effective for a,a-alkyl-aryl aldehydes 62a-d (up to 60% yield and up to 90% ee).…”

Reduction of hydrazines to amines with low-valent titanium reagent

“…1 Among various methods for the synthesis of amines, hydrazines often appear as key intermediates. [2][3][4][5][6][7][8][9][10][11][12] Remarkable examples are the addition of alkylzinc reagent to arylazo tosylates, 12 electrophilic addition of -diazoesters with ketones, 13 the addition of carbon nucleophiles to azodicarboxylates 14 and acylhydrazonium salts, 15 the anionic 8,16 or radical 17 additions to the C=N bond of hydrazones, the cross-coupling of ketones with hydrazones, 18 the addition of N-aminolactams to Michael acceptors, 10,19 the aza-Michael addition of hydrazines to electrophilic alkenes, 20 the radical cyclization of N-allyl--perchlorohydrazides, 21 and the 1,3-dipolar cycloaddition of azomethine imines to dipolarophiles. 22 These examples clearly show the significance of N,N bond cleavage in organic synthesis.…”

Atroposelective Organocatalysis

“…Chiral thioureas [16] and hydrogen-bond networks [16] can be used in new reaction methodologies, that is, combining foldamers with established principles in organocatalysis can be applied to atroposelective reactions. [17] …”