Direct reductive amination

The direct reductive amination (DRA) is a useful method for the synthesis of amino derivatives from carbonyl compounds, amines, and H2. Precious-metal (Ru [130-132], Rh [133-137], Ir [138-142], Pd [143]) catalyzed reactions are well known to date. The first Fe-catalyzed DRA reaction was reported by Bhanage and coworkers in 2008 (Scheme 42) [144]. Although the reaction conditions are not mild (high temperature, moderate H2 pressure), the hydrogenation of imines and/or enam-ines, which are generated by reaction of organic carbonyl compounds with amines, produces various substituted aryl and/or alkyl amines. A dihydrogen or dihydride iron complex was proposed as a reactive intermediate within the catalytic cycle. 

Scheme 42 Direct reductive amination of organic carbonyl compounds...

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358... 

The sequence tropone (e.g., 391) to imine to amine to endimine (e.g., 585) can occur in a one-pot reaction (80SAP7807011). An example of a more direct reductive amination is the formation of piperazino derivative 586 from 401 (88WOP8803138). 

This protocol led to the diamine 46, which also represents a protected amino sugar (2,4-diamino-2,4-dideoxy-L-xylose). Interestingly, the direct reductive amination of 47 was followed by in situ cyclization to afford the lactam 48 as the major diastereomer. 

Reduction ofimines. A mixture of Bu SnClj and Bu SnHj generates BujSnfCljH which saturates imines when complexed with HMPA. Thus, a-amino ketones are obtained from the corresponding imino ketones. Direct reductive amination of carbonyl compounds is also achieved (11 examples, 70-99%). ... 

At this point, we investigated the reduction of the ketone to the phenethyl alcohol followed by Mitsunobu displacement as well as direct reductive amination. We were able to efficiently reduce the ketone racemically using NaBH4 in MeOH to alcohol 32. However, the subsequent Mitsunobu reaction proved problematic and no desired product was observed (Scheme 5.12). 

Aldehydes cannot undergo direct enantioselective reduction due to the formation of an achiral product, but List s group discovered an interesting variation on this theme with the direct reductive amination of a-branched aldehydes via an efficient dynamic kinetic resolution (DKR) [56]. Under the reductive amination conditions, an a-branched aldehyde undergoes a fast racemization in the presence of the amine and acid catalyst via an imine/enamine tautomerization. The reductive amination of one of the two imine enantiomers would then have to be faster than that of the other, resulting in an enantiomerically enriched product via a dynamic kinetic resolution (Figure 15.6). TRIP once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine product in 50%... 

Fig. 10.1 Dual activation role of iodine in direct reductive amination (DRA)...

The direct reductive amination of aromatic aldehydes has been achieved with excellent yields using a gold(I) catalyst along with a Hantzsch ester as the hydrogen source under mild reaction conditions [154]. In another example, B(C6F5)3- is shown to act as a catalyst for the transfer of hydrogen from a Hantzsch ester to an imine [155]. 

A carbene derived from triazole was used in IPA with K2CO3 as base, for direct reductive amination of aldehydes with primary amines to form secondary amine products [179]. Other recent examples include (1) a base-free catalyzed reduction of a series of C=0 bonds and of the C=N bond of benzylideneaniline (>99 % conversion was achieved in 48 h, with 0.1 mol% catalyst) [180] (2) heteroditopic dicarbene Rh(I) and Ir(I) complexes containing 1,2,3-triazolylidene-imidazolyli-dene ligands, mostly tested on acetophenone but with one imine example [181] (3) Ir complexes of A-benzyl-substituted A-heterocyclic carbenes where 0.5 mol% catalyst is used with 5 % KOH in IPA in reductions to give products in >99 %... 

Sc(OTf)3 was used in direct reductive amination reactions using one of Hantzsch dihydropyridines as a reducing reagent [88]. In particular, the selective reaction of the aldehyde-derived imine was carried out with the coexistence of other reducible functional groups including ketones [89]. Intramolecular hydroamination could also finely be performed using Sc complexes [90]. 

Two different routes for the biosynthesis of L-lysine are known in microorganisms. The a-aminoadipate route (AA), of which two variants are known, which start from 2-oxoglutarate and acetyl-CoA [23]. The three variants of the diaminopime-late route (DAP), which starts from L-aspartate, can be distinguished by their use of either succinylated or acetylated intermediates or by direct reductive amination of tetrahydropicolinate [24]. 

The direct reductive amination of aldehydes with primary or secondary amines using a catalytic amount of Pd(PhCN)2Cl2 and 2,2 -biquinoline-4,4 -dicarboxylic acid dipotassium salt (BQC) in water under 200 psi of H2 afforded secondary or tertiary amines. In some cases, primary alcohols were formed as byproducts (eq 168). ... 

Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by P-ehmination gave the enone 13. Direct reductive amination of 13 failed, hut reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile 3. 

Many prefer to address the latter protocol as the reductive amination in the true sense and not the first one as it requires the isolation of the imine intermediate, which is infamous for its limited stability and the reversibility of its formation. The direct reductive amination has gained a lot of attention from both the worlds of academia and industries as it gives access to direct amine products in one step from the carbonyl compounds, thereby saving one step in the total synthesis scheme, which is atom-economic and thus financially profitable. 

Tararov VI, Kadyrov R, Riermeier TH, Fischer C, Bomer A. Direct reductive amination versus hydrogenation of inter-mediates-a comparison. Adv. Synth. Catal. 2004 346 (5) 561-565. 

Menche D, Arikan F, Li J, Rudolph S. Directed reductive amination of (3-hydroxy-ketones convergent assembly of the ritonavir/lopinavir core. Org. Lett. 2007 9(2) 267-270. 

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