Abstract:An enantioselective hydrogenation of fluorinated hydrazones has been achieved by employing [Pd(R)-DTBM-SegPhos(OCOCF3)2] as the catalyst, providing a general and convenient method toward chiral fluorinated hydrazines. A broad substrate scope including β-aryl-, γ-aryl-, and alkyl-chain-substituted hydrazones worked efficiently in high yields and up to 94% of enantioselectivity. The reductive amination between trifluoromethyl-substituted ketones and benzohydrazides could also proceed smoothly.
“…Additives in DARA reactions have been proven to be perfectly competent in improving both reaction reactivity and selectivity significantly 31 – 44 , 56 – 58 . Titanium isopropoxide is well known to be able to facilitate the formation of the imine intermediates 59 .…”
Section: Resultsmentioning
confidence: 99%
“…Apart from the intramolecular DARAs 16 – 23 , most reported N-sources of DARAs generally fall into three categories: inorganic ammonium salts 24 – 29 /ammonia 30 for the synthesis of primary amines; aryl amines 31 – 35 , the popularly applied N-sources, albeit often times the N -Ar group in the product is not desired and needs to be removed, which lead to secondary chiral amine products; and one example of secondary amine sources for the construction of tertiary chiral amine products 36 . Besides, there are some other sporadically reported special amines, including benzyl amines 37 , 38 , diphenylmethylamine 39 – 41 , hydrazine 42 , and hydrazides 43 , 44 . Fig.…”
Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.
“…Additives in DARA reactions have been proven to be perfectly competent in improving both reaction reactivity and selectivity significantly 31 – 44 , 56 – 58 . Titanium isopropoxide is well known to be able to facilitate the formation of the imine intermediates 59 .…”
Section: Resultsmentioning
confidence: 99%
“…Apart from the intramolecular DARAs 16 – 23 , most reported N-sources of DARAs generally fall into three categories: inorganic ammonium salts 24 – 29 /ammonia 30 for the synthesis of primary amines; aryl amines 31 – 35 , the popularly applied N-sources, albeit often times the N -Ar group in the product is not desired and needs to be removed, which lead to secondary chiral amine products; and one example of secondary amine sources for the construction of tertiary chiral amine products 36 . Besides, there are some other sporadically reported special amines, including benzyl amines 37 , 38 , diphenylmethylamine 39 – 41 , hydrazine 42 , and hydrazides 43 , 44 . Fig.…”
Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.
“…Over the recent fifteen years, palladium complexes have been successfully applied in asymmetric hydrogenation of various prochiral substrates bearing C=N double bond, including hydrazones . Considerable advances in this field and our previous experience prompted us to study an application of palladium catalysis for the synthesis of optically active α ‐amino phosphonates using α ‐hydrazono phosphonates as convenient precursors.…”
Section: Figurementioning
confidence: 99%
“…It is known that TFE serves as a “magic” solvent in homogeneous enantioselective Pd‐catalyzed hydrogenation –. However, it has been shown that its dilution with such low‐polarity solvents as toluene or dichloromethane have had a good effect in some cases.…”
An efficient and convenient one-pot procedure for the stereoselective catalytic synthesis of ring-substituted [amino(phenyl)methyl]phosphonates has been developed. The enantioselective hydrogenation of easily available diisopropyl (Z)-[aryl(phenylhydrazono)methyl]phosphonates using palladium(II) acetate as a precatalyst, (R)-2,2'-bis (diphenylphosphino)-5,5'-dichloro-6,6'-dimethoxy-1,1'-biphenyl [(R)-Cl-MeO-BIPHEP] as a ligand, and (1S)-(+)-10-camphorsulfonic acid as an activator in a mixture of 2,2,2-trifluoroethanol and methylene chloride at ambient temperature results in the formation of corresponding [aryl(2-phenylhydrazino)methyl]phosphonates. The subsequent cleavage of the NÀN bond has been accomplished with molecular hydrogen after the addition of palladium on carbon and methanol into crude reaction mixture to afford the optically active [amino(aryl)methyl]phosphonates. The method is operationally simple and provides an appreciable enantioselectivity up to 98 % ee.Keywords: a-amino phosphonates; asymmetric catalysis; a-hydrazono phosphonates; hydrogenation; palladium a-Amino phosphonates, particularly nonracemic ones, have been a topic for decades due to a wide spectrum of their possible applications.[1] Nevertheless, the stereocontrolled formation of a-amino phosphonates remains a challenge in chemical synthesis. Among catalytic concepts for the enantioselective synthesis of a-amino phosphonates, two methodologies are leading, namely, asymmetric hydrophosphonylation of aldimines and ketimines and asymmetric reduction of a,b-dehydroaminophosphonates.[2] Several years ago we reported on the feasibility of Rh-catalyzed asymmetric hydrogenation of a-imino phosphonates as a straightforward access to optically active a-amino phosphonates containing the quaternary b-carbon atom.[3] Subsequently, this approach was extended on oxazaborolidine catalyzed reduction of (2,2,2-trifluoro-1-iminoethyl)phosphonates with catecholeborane.[4] Along with all apparent advantages, some pitfalls of this method should be mentioned. First, aimino phosphonates are actually an equilibrium mixture of Z/E-isomers, which may have an adverse effect on the overall stereoselectivity of the process. In addition, these starting substrates are slowly hydrolyzed on storage. Finally, the common synthesis of aimino phosphonates via the Michaelis-Arbuzov rearrangement requires the usage of labile imidoyl chlorides under harsh reaction conditions.[5] When the present paper was in preparation, Zhou et al. communicated on excellent results in Pd-catalyzed asymmetric hydrogenation of a-tosylimino phosphonates. [6] However, the latter precursors cannot be considered the best choice, because they are synthesized from the same racemic a-tosylamino phosphonates by N-chlorination/dehydrochlorination procedure. [7] Readily accessible a-oxo phosphonates [8] are important reagents for the preparation of elaborate phosphonates. Unfortunately, they cannot be used for the synthesis of the corresponding a-imino phosphonates since the interaction of si...
“…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.…”
A new class of axial-chiral biisoquinoline N,N′-dioxides was evaluated as catalysts for the enantioselective hydrosilylation of acyl hydrazones with trichlorosilane. While these catalysts provided poor to moderate reactivity and enantioselectivity, this study represents the first example of the organocatalytic asymmetric reduction of acyl hydrazones. In addition, the structures and energies of two possible diastereomeric catalyst–trichlorosilane complexes (2a–HSiCl3) were analyzed using density functional theory calculations.
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