Iridium-catalyzed direct asymmetric reductive amination of aromatic ketones

Abstract

Diphenylmethanamine offers excellent stereocontrol and easy deprotection to provide primary amines in the studied asymmetric reductive amination.

Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine

“…In the first step, esterification between compound 1 and 2 was carried out under mild conditions to afford 3 in quantitative yield, which is the key intermediate and substrate for next step. On the basis of our group’s early work [ 21 , 22 , 23 ], the catalytic system of iridium–monodentate phosphoramidite and a few additives were adopted. The monodentate phosphoramidite chiral ligands are based on BINOL back-bone, which is a cheap and readily available bulk chemical.…”

“…Efficient and practical asymmetric synthesis of rivastigmine is still highly desired. Recently we have demonstrated that diphenylmethylamine is a universal amine source for the direct asymmetric reductive amination (DARA) of various ketones, catalyzed by iridium and readily available phosphoramidite ligand based on BINOL [ 21 , 22 , 23 ]. Here we report the convenient synthesis of ( S )-rivastigmine applying the DARA strategy.…”

Iridium-catalyzed direct asymmetric reductive amination utilizing primary alkyl amines as the N-sources

“…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 .

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“…Previously there was only one example that utilized an alkyl amine, MeNH 2 , as the N -coupling partners in transition-metal-catalyzed DARAs 45 , and some instances in which special alkyl amines, such as benzyl amines 38 , 39 diphenylmethylamine 39 – 41 , and allylamine 46 , were used. Even the literature for the asymmetric hydrogenation of corresponding N -alkyl imines to directly form the N -alkyl amines are extraordinary scarce 47 – 52 , of which in two cases the N -alkyl amines were in situ transformed into N -SiH 2 Ph and N -Boc products in order to decrease the inhibitory effects on the catalysts 49 – 51 .…”

Synthesis of Potent Calcimimetics (+)-NPS R-568 by Palladium-Catalyzed Oxidative Kinetic Resolution

“…A few literature reports are available for the enantioselective synthesis of 1, in which the chiral center was developed by chiral poll approach [6,7,8], asymmetric hydrosilylation of imine [9,10,11], asymmetric reductive acylation of a ketoxime [12], diastereoselective addition of Grignard reagent [13], organolithium and dimethylzinc to imines bearing a chiral auxiliary [14,15,16], reductive amination of aromatic ketone [17,18,19], diastereoselective Nalkylation of amines with racemic alcohol [20,21], chiral ligand-promoted cobalt-catalysed radical hydroamination of alkene [22] or enantioselective arylation of aliphatic imines [23]. However, most of these methods have several drawbacks, such as tedious and time consuming experiments, unavailability or expensive chiral starting materials, low yield and lower enantiomeric purity, etc.…”