Chiral Phosphoric Acid-Catalyzed Asymmetric Transfer Hydrogenation of Quinolin-3-amines

Abstract

A chiral phosphoric acid catalyzed asymmetric transfer hydrogenation of aromatic amines, quinolin-3-amines, was successfully developed with up to 99% ee. To supplement our previous work on the Ir-catalyzed asymmetric hydrogenation of 2-alkyl substituted quinolin-3-amines, a number of 2-aryl substituted substrates were reduced to provide a series of valuable chiral exocyclic amines with high diastereo-and enantioselectivities.O ptically active exocyclic amines exist as key structural elements in many biologically active molecules including natural and unnatural products.1 In addition, they are useful intermediates for organic synthesis and serve as chiral catalysts in various asymmetric transformations. Due to the simplicity and atom efficiency, asymmetric catalytic reduction of exocyclic enamines, imines, and aromatic amines represents a significant approach to these compounds.2 Compared to the various successful examples of the asymmetric hydrogenation of exocyclic enamines and imines, 1,3 little attention has been paid to the asymmetric hydrogenation of aromatic amines due to their high stability of aromaticity and strong coordinating ability. However, catalytic asymmetric hydrogenation of other heteroarenes has been well documented. 4−10Very recently, we reported the first asymmetric hydrogenation of aromatic amines, 2-alkyl substituted quinolin-3-amines, giving the chiral exocyclic amines in excellent yields, with high diastereo-and enantioselectivities.11 However, for the 2-aryl substituted substrate, only a moderate ee value was obtained. In consideration of the successful application of chiral phosphoric acids (CPA) in the asymmetric transfer hydrogenation of CC, CN, and CO double bonds and heteroaromatic compounds with Hantzsch esters (HEH) 12−14 as the hydrogen source, we envision that quinolin-3-amines could also be enantioselectively reduced using this catalyst system (Scheme 1). As a part of our sustained efforts in the asymmetric hydrogenation of aromatic compounds, 4a,b,f and also as a supplement to our previous work, 11 herein, we report an efficient CPA-catalyzed transfer hydrogenation of 2-aryl substituted quinolin-3-amines with excellent diastereo-and enantioselectivities.Initially, 2-phenylquinolin-3-amine was selected as the model substrate. The original experiment was conducted in 1,4-dioxane by using CPA (S)-3a as the catalyst and HEH 2a as the hydrogen source. Unfortunately, no reaction was observed (Scheme 2). Then, the effect of the N-protecting groups of 2-phenylquinolin-3-amine on the reactivity and enantioselectivity was investigated. Several protecting groups were introduced to the amino group, and to our delight, the desired products could be obtained for both the tert-butoxycarbonyl group (Boc) and p-toluenesulfonyl group (Ts) protected substrates while the phthaloyl group (Phth) failed to promote the reaction. The Ts group protected substrate 4-methyl-N-(2-phenylquinolin-3-

Divergent Coupling of Anilines and Enones by Integration of C−H Activation and Transfer Hydrogenation

“…On the basis of our observations,wepropose the following iridium(III)-catalyzed TH-coupling [15] mechanism (Scheme 8): C À Ha ctivation of aniline 1 gives iridacycle E together with HX. Coordination and insertion of an enone into the Ir À Ar bond generates an Ir III alkyl complex F in equilibrium with hydride G through b-H elimination.…”

“…[3b] With the same Ir III catalyst and the PivOH additive,the reaction of 1a and EVK afforded 5aa as the major product through TH in isopropanol, [15] and the yield was optimal when Ni(OAc) 2 was introduced (Scheme 3, conditions B). Te trahydroquinolines have also been prepared in racemic form or enantioselectively by the hydrogenation of quinolines.…”

“…[*] X. Zhou reaction of 1a and EVK afforded 5aa as the major product through TH in isopropanol, [15] and the yield was optimal when Ni(OAc) 2 was introduced (Scheme 3, conditions B). Anilines bearing electron-donating and electron-withdrawing groups at different positions all coupled smoothly to afford the tetrahydroquinolines 5ba-ra in moderate to good yields.T he scope of the reaction with respect to the enone substrate was also broad, although the alkyl group in the enone had great influence on the reaction efficiency (products 5ab-af).…”

Catalytic Asymmetric Transfer Hydrogenation of Imines: Recent Advances

“…The ATH has also been applied to functionalized quinolines in order to diastereo‐ and enantioselectively prepare tetrahydroquinolines. Thus, this methodology was used for quinolines bearing sulfonamido, trifluoromethyl, nitro, or fluoro substituents mainly at the 3‐position, working with a Hantzsch ester 79 and a phosphoric acid 78 with different substitution at the 3‐ and 3′‐positions. In general, yields, diastereo‐ and enantioselectivities were high.…”

A Petal-type Chiral NADH Model: Design, Synthesis and its Asymmetric Reduction

“…Since the pioneering work reported by Ohno and his co-workers in 1975 4 , many NADH models received particular attention and were widely explored in the past few decades 5 6 7 . Recently, Hantzsch esters have been widely and successfully used as reductant in the enantioselective transfer hydrogenation of unsaturated bonds with chiral catalyst, such as C=C and C=N, which can be successfully reduced in high yields under mild conditions 8 9 10 11 12 13 . However, compared to the various examples of catalytic asymmetric transfer hydrogenation reactions of C=C and C=N double bonds mediated by Hantzsch esters, fairly limited work has been reported on asymmetric hydrogenation reactions of C=O double bonds by chiral NADH models 13 .…”