Rhodium‐Catalyzed Chemo‐ and Enantioselective Hydrogenation of Alkynyl‐Aryl Hydrazones

Abstract

As an update of our continuous interest in the hydrogenation of hydrazones, a chemo-and enantioselective hydrogenation of alkynyl-aryl hydrazones was developed using a rhodium complex [Rh((R,Sp)-JosiPhos)(cod)]SbF 6 as the catalyst and benzoic acid as an additive. Directed by a pnitrobenzamido group, the chiral propargyl hydrazines, which can be easily converted to chiral propargylamines of significant importance and potential use, were obtained with good yields, excellent chemoselectivities and good to excellent enantioselectivities. Although the enantioselectivity of the reaction and the substrate/catalyst ratio require further refinement, the reported methodology provides an alternative route for the efficient preparation of chiral propargylamines. Chiral propargylamines are versatile intermediates for the synthesis of numerous important pharmaceuticals and bioactive compounds. Thus, their asymmetric catalytic syntheses have attracted much attention. The asymmetric synthesis of such compounds can be realized via construction of CÀC and CÀN bonds or through reduction of C=C and C=N bonds. The asymmetric addition of terminal alkynes to imines is one of the most studied methodologies for the synthesis of chiral propargylamines. [1] Additionally, the asymmetric addition of alkyl or aryl reagents to alkynyl imines has also been investigated. [2] The asymmetric amination of propargylic esters provides another route to the target products. [3] However, these methodologies are not practical for large scale application due to low reaction activity, the need for a high catalyst loading and difficulties encountered when scaling up the reactions. On the other hand, asymmetric hydrogenation, [4] as the most practical process for its high efficiency, environmental friendliness, and low economic cost, has also been applied to the synthesis of chiral propargylamines. However, there is only one example concerning the reduction of an a-alkynyl enaminde to give the corresponding methyl-substituted chiral propargylamine. [5] To the best of our knowledge, an alternative route that employs the asymmetric hydrogenation of a-alkynyl imines has not been previously studied. The absence of such a methodology is related to the difficulty in developing reactions that are both highly chemo-and enantioselective. [6] In continuation of our research on rhodiumcatalyzed asymmetric hydrogenation reactions, [7] we have developed a chemo-and enantioselective hydrogenation of aryl-alkenyl hydrazones assisted by an amido directing group. [7c] Using a similar strategy, we herein report the chemo-and enantioselective hydrogenation of alkynyl-aryl hydrazones for the efficient synthesis of chiral propargylamine derivatives (Scheme 1).Firstly, a number of N-NHBz-substituted alkynylaryl hydrazones 1-Silyl bearing terminal silyl groups were prepared and tested in the asymmetric hydrogenation using [Rh(cod) 2 ]SbF 6 /(R,R)-QuinoxP* as the catalytic system (Table 1). Compared to C-based

Ruthenium-Catalyzed Enantioselective Hydrogenation of Hydrazones

“…Since this initial report, many excellent examples of enantioselective hydrazone reduction have been disclosed (Scheme B). Following the work of Burk, many of these reports employ the use of rhodium based catalysts, with fewer examples of palladium, nickel, iridium, and cobalt based catalysts. Despite the great success of ruthenium catalysts in related imine reduction chemistry, to the best of our knowledge there are no examples of utilizing group 8 metals in hydrazone reduction.…”

“…The vast majority of enantioselective hydrazone reductions utilize benzoyl-protected hydrazones as substrates. − Interestingly, this commonly employed protecting group does not achieve high levels of enantioselectivity under the standard ruthenium-catalyzed conditions, leading to benzoyl-protected hydrazine 21 in good yield but with only moderate enantioselectivity. To further probe this observation, electronically differentiated benzoyl-protected hydrazones were prepared and subjected to the standard reaction conditions.…”

A diversity of recently reported methodology for asymmetric imine reduction

“…24). 29 A variety of substrates containing triple bonds were converted to chiral amines without affecting the alkyne. Furthermore, this protocol gives easy access to chemically important structure motifs, i.e.…”

Evaluation of 3,3′-Triazolyl Biisoquinoline N,N′-Dioxide Catalysts for Asymmetric Hydrosilylation of Hydrazones with Trichlorosilane

“…Since this initial breakthrough, many excellent transition metal-catalyzed methods for the asymmetric reduction of hydrazones have been developed. The majority of these examples utilized rhodium-based catalysts [3][4][5][6][7][8][9][10][11][12][13] but palladium- [14][15][16][17], iridium- [18], ruthenium- [19], nickel- [20][21][22][23] and cobalt- [24] based catalysts are also reported (Scheme 1, Equation ( 1)). While their reaction scopes are impressive, no metal-free 'green' counterpart (i.e., organocatalysis method) has been reported to the best of our knowledge, except for two scattered examples.…”