Iridium‐Catalyzed Asymmetric Hydrogenation of Quinoline Derivatives with C₃*‐TunePhos

Abstract

A series of C 3 *-TunePhos chiral diphosphine ligands has been successfully applied in the iridium-catalyzed enantioselective hydrogenation of quinolines, and this methodology provided an efficient access to a variety of optically active tetrahydroquinolines with up to 93% ee. Furthermore, attempts on the asymmetric hydrogenation of quinoline N-oxide are also discussed.Keywords: asymmetric catalysis; enantioselectivity; hydrogenation; iridium; quinolines The direct catalytic asymmetric hydrogenation of quinolines constitutes the most convenient route to enantiomerically pure tetrahydroquinolines, [1] which are not only useful synthetic intermediates [2] but also structural moieties in alkaloids which are natural products and biologically active compounds.[3] The first example of asymmetric hydrogenation of quinolines was reported by Zhou [4a] and co-workers, and some progresses has been achieved thereafter. [4][5][6] However, the challenges of developing easily accessible, air-stable, chiral ligands and their application in the direct asymmetric hydrogenation of highly substituted quinolines still remain.In previous communications, we have developed a practical and convenient synthetic route to prepare a series of air-stable, modular, biaryl chiral diphosphine ligands C 3 *-TunePhos (Scheme 1).[7] These ligands were designed to achieve superior enantioselectivities for asymmetric hydrogenations utilizing the highly modular nature of their unique steric and electronic properties and they have been demonstrated to be highly effective in the hydrogenation N-substituted allylphthalimides, [7g] b-keto esters [7h] and unfunctionalized ketones.[7i] Chan et al. demonstrated the catalytic capability of (S),A C H T U N G T R E N N U N G (S,S)-1b for the iridium-catalyzed reduction of some heteroaromatic compounds, [7j] however, hard modifications on P-aryl groups restrict their potential applications, since for atropisomeric biaryldiphosphines, a small variation of the dihedral angle of the ligands can have a significant impact on the reactivity and selectivity of the reaction. Thus, to screen the catalytic performance of C 3 *-TunePhos families and illustrate their potential utilities, we summarized our efforts in the iridium-catalyzed asymmetric hydrogenation of highly substituted quinoline derivatives.Our initial study began with hydrogenation of 2-methylquinoline 1a as the model substrate and a brief screening of the performance of different catalysts.

Strong Brønsted acid promoted asymmetric hydrogenation of isoquinolines and quinolines catalyzed by a Rh–thiourea chiral phosphine complex via anion binding

“…As far as we know, few catalytic systems can be applied for asymmetric hydrogenation of both isoquinolines and quinolines with both high turn-overs and excellent enantioselectivities. 7 , 8 Then a question came to us: can this synthetic protocol be used to synthesize chiral THQs with high ee? By employing the optimized condition (DCM/iPrOH = 2 : 1, v/v) in the case of asymmetric hydrogenation of isoquinolines, we found that the enantioselectivity was dramatically increased to 99% ee.…”

“…To the best of our knowledge, however, asymmetric hydrogenation of N-heteroaromatics, especially isoquinolines, remains a challenging task. 7 Although quinolines have been successfully hydrogenated in several cases, 8 there are only a few examples of isoquinolines. Zhou's group used an iridium–bisphosphine catalyst to obtain high enantioselectivity, but this transformation needs activation by chloroformate or the addition of BCDMH.…”

Asymmetric Hydrogenation of Imines

“…Later, in the study of the hydrogenation of N-aryl imines by Zhang and co-workers, iodine was chosen as the additive to promote this catalytic process. Thus, following this pioneering work, iodine has also been studied extensively and found to have significant enhancing effects to both enantioselectivity and reactivity in the Ir-catalyzed hydrogenation of imines [36,48] and of other closely-related substrate types, including enamines [89,90], quinoline derivatives [91][92][93][94][95], quinoxalines [96], and other heteroaromatics [97][98][99][100]. Representative examples of iodide compounds and iodine as effective additives in enantioselective imine hydrogenations are summarized in Table 1.…”

Additive Effects of Amines on Asymmetric Hydrogenation of Quinoxalines Catalyzed by Chiral Iridium Complexes

“…[1] Asymmetric hydrogenation of N-heteroaromatic compounds is considered to be a difficult task due to aromatic resonance stability. Recent developments in asymmetric hydrogenation of N-heteroaromatic compounds, [2] such as 2-substituted quinolines [3][4][5][6][7][8][9][10][11][12][13][14][15] and quinoxalines [3h, k, 4c, f, 11, 16-22] (to give the 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroquinoxaline derivatives, respectively, in high enantioselectivity), pyridine derivatives, [3h, 4g, 23] pyr-roles, [24] imidazole, [25] oxazole, [25] and indoles, [26] have been remarkable. However, only a few mechanistic studies of the asymmetric hydrogenation of N-heteroaromatics have been reported.…”