Palladium‐Catalyzed Asymmetric Hydrogenation of Simple Ketimines Using a Brønsted Acid as Activator

Abstract

Using a catalytic amount of a Brønsted acid as activator of simple imines, the highly enantioselective homogeneous palladium-catalyzed asymmetric hydrogenation of simple ketimines was successfully developed with up to 95% ee.Keywords: asymmetric hydrogenation; Brønsted acids; ketimines; palladium catalysisThe preparation of chiral amines from the transition metal-catalyzed asymmetric hydrogenation or transfer hydrogenation of prochiral imines represents one of the most direct and efficient approaches that open a straightforward route to valuable building blocks for natural products, pharmaceuticals and other fine chemical compounds.[1] A variety of chiral metal catalysts has been successfully applied to this reaction over the last few decades. Among the various catalytic systems so far, Ru, [2] Rh, [3] Ir [4] and organocatalysts [5] have been successfully employed in enantioselective hydrogenations and/or transfer hydrogenations of imines. Recently, Zhang and co-workers developed the first asymmetric hydrogenation of unprotected N À H iminiums with up to 95% ee using chiral iridium complexes as catalyst.[6] Although significant progress have been made in the enantioselective reduction of imines, the search for new catalytic systems is still highly desirable.Pd-based catalytic systems have been extensively employed for a wide range of useful synthetic organic transformations, [7] nevertheless, very little attention has been paid to homogeneous asymmetric hydrogenation with chiral Pd complexes. The asymmetric hydrogenations of a-phthalimide ketones and a-keto phosphonates with palladium catalyst systems were reported by us [8] and Goulioukina, [9] respectively. In comparison, there are more reports on Pd-catalyzed asymmetric hydrogenations of activated imines. The first hydrogenation of imino esters catalyzed by palladium complexes was described by Amii [10] and coworkers with up to 91% ee in 2001. Afterwards, highly enantioselectively Pd-catalyzed hydrogenations of N-diphenylphosphinyl ketimines and N-tosylimines were reported by us [11] and the Zhang [12] group, respectively [Scheme 1, Eq. (1)]. Since then, chiral palladium complexes have also been employed for the asymmetric hydrogenation of some other cyclic activated sulfonylimines in our laboratory. [13] In 2009, Rubio-PØrez [14] and co-workers reported the direct reductive amination of alkyl ketones catalyzed by chiral palladium complexes at 70 8C with up to 99% ee, but only moderate yield and low enantiomeric excess were observed in the amination of aryl ketones. Most recently, an efficient Pd-catalyzed asymmetric hydrogenation of simple indoles was developed by us with a Brønsted acid as activator.[15] Although much effort Scheme 1. Activation strategy for Pd-catalyzed asymmetric hydrogenation of simple ketimines.

Silver nanoparticles supported on alumina–a highly efficient and selective nanocatalyst for imine reduction

“…14 Within these methods, the homogeneous transition metal-catalyzed oxidative dehydrogenation of alcohols to carbonyl compounds that can form an imine by condensation with an amine is an attractive synthetic approach due to high atom efficiency. [15][16][17][18][19] Nevertheless, these homogeneous catalysts suffer from drawbacks such as difficulty in recovery and reuse of expensive metals, necessity of special handling of metal complexes, and the required use of co-catalysts such as a base promoter and a stabilizing ligand. Hence, the application of efficient, easily recoverable heterogeneous catalysts which are relatively inexpensive, would clearly be advantageous.…”

Asymmetric Hydrogenation of Imines

“…In 2001, Norton demonstrated the first catalytic enantioselective hydrogenation of N-benzylimine through an ionic mechanism with the assistance of HBF 4 and achieved 66% ee [118]. Later, it was reported that the introduction of an acid activator could be achieved by preforming iminium type substrates such as N-H imines [43,119], or by the addition of the acid activator in situ [120,121]. Following that strategic breakthrough, groundbreaking works of Pd-catalyzed asymmetric hydrogenation of heteroaromatics, such as unprotected indoles by Zhou et al, and pyrroles by Zhou, Fan et al were recently published [115,122,123].…”

“…Using Pd(CF 3 COO) 2 as the Pd precursor, in TFE, C 4 -TunePhos was found to be the most effective biaryl diphosphine ligand in affording the corresponding chiral amines at up to 95% ee (Scheme 39) [120]. A series of Brønsted acid studied in this reaction and D-DTTA was found to be the best additive in terms of enantioselectivity.…”

“…Moreover, the hydrogenation of such iminium salt substrates under acidic conditions could also help suppress the inhibitory effects of corresponding amine products. This "acidic activation strategy" has recently encouraged successful examples of asymmetric hydrogenation of imine substrates [120,121] and heteroaromatics [115,122,123]. Furthermore, the preparation of N-H imines is readily accessible via organometallic addition to nitriles followed by quenching with anhydrous MeOH and isolation of the corresponding bench-stable hydrochloride salts.…”

Homogeneous palladium-catalyzed asymmetric hydrogenation

“…25 The addition of Brønsted acid could not only play a great part in the activation of the substrate, but also reduce the inhibitory effect of the substrate on the palladium catalyst the same as the electron-withdrawing group played. Interestingly, this protocol was more effective for the asymmetric hydrogenation of ketimines derived from tetralone than that from simple acetophenones (Scheme 9).…”