Imine Reduction and Reductive Amination

1 Metal-free reduction of mines enantioselective bronsted acid catalyzed 

TRANSFER HYDROGENATION USING CHIRAL BINOL-PHOSPHATES AS CATALYSTS. 162 

2 Metal-free bronsted aqd catalyzed transfer-hydrogenation  

Catalysts for Fine Chemical Synthesis, Vol. 5 Regio- and Stereo-Controlled Oxidations and Reductions Edited by S. Roberts and J. WhittaU 2007 John Wiley Sons, Ltd 

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The adduct (404, R =R =H) has been oxidised with dichlorodi-cyanobenzoquinone to the quinone imine (405) and the amine (406), both of which have been oxidised to the ortho-quinone and this on reduction affords both the trans-diol (407) and... 

Sodium cyanoborohydride is remarkably chemoselective. Reduction of aldehydes and ketones are, unlike those with NaBH pH-dependent, and practical reduction rates are achieved at pH 3 to 4. At pH 5—7, imines (>C=N—) are reduced more rapidly than carbonyls. This reactivity permits reductive amination of aldehydes and ketones under very mild conditions (42). 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

Amin omethyl-3,5,5-trimethyl cyclohexyl amine (21), commonly called isophoronediamine (IPD) (51), is made by hydrocyanation of (17) (52), (53) followed by transformation of the ketone (19) to an imine (20) by dehydrative condensation of ammonia (54), then concomitant hydrogenation of the imine and nitrile functions at 15—16 MPa (- 2200 psi) system pressure and 120 °C using methanol diluent in addition to YL NH. Integrated imine formation and nitrile reduction by reductive amination of the ketone leads to alcohol by-product. There are two geometric isomers of IPD the major product is ds-(22) [71954-30-5] and the minor, tram-(25) [71954-29-5] (55). 

Reductive amination has been successfully applied to the preparation of tertiary fflnines from carbonyl compounds and secondary amines even though a neutral imine is not possible in this case. 

Reductive amination takes place by the pathway shown in Figure 24.4. An imine intermediate is first formed by a nucleophilic addition reaction (Section 19.8), and the C=N bond of the imine is then reduced. 

Active Figure 24.4 MECHANISM Mechanism of reductive amination of a ketone to yield an amine. Details of the imine-forming step were shown in Figure 19.8 on page 711. Sign in afwww.thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

Reduction of iV-(3-bromopropyl) imines gives a bromo-amine in situ, which cyclizes to the aziridine. Five-membered ring amines (pyrrolidines) can be prepared from alkenyl amines via treatment with N-chlorosuccinimide (NCS) and then BusSnH. " Internal addition of amine to allylic acetates, catalyzed by Pd(PPh3)4, leads to cyclic products via a Sn2 reaction. Acyclic amines can be prepared by a closely related reaction using palladium catalysts. Three-membered cyclic amines (aziridines)... 

The reductive amination of ketones can be carried out under hydrogen pressure in the presence of palladium catalysts. However, if enantiopure Q -aminoketones are used, partial racemization of the intermediate a-amino imine can occur, owing to the equilibration with the corresponding enam-ine [102]. Asymmetric hydrogenation of racemic 2-amidocyclohexanones 218 with Raney nickel in ethanol gave a mixture of cis and trans 1,2-diamino cyclohexane derivatives 219 in unequal amounts, presumably because the enamines are intermediates, but with excellent enantioselectivity. The two diastereomers were easily separated and converted to the mono-protected cis- and trans- 1,2-diaminocyclohexanes 220. The receptor 221 has been also synthesized by this route [103] (Scheme 33). 

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. 

Aromatic aldehydes can be reductively aminated with the combination Zn(BH4)2-ZnCl2,97 and the ZnCl2 assists in imine formation. 

Amines can be synthesized by the treatment of a ketone or aldehyde with an amine in the presence of hydrogen and a noble metal catalyst. During this reductive amination, the intermediate loses water to give an imine that is reduced to yield the amine product (Scheme 5.4). 

Nitro compounds are versatile precursors for diverse functionalities. Their conversion into carbonyl compounds by the Nef reaction and into amines by reduction are the most widely used processes in organic synthesis using nitro compounds. In addition, dehydration of primary nitro compounds leads to nitrile oxides, a class of reactive 1,3-dipolar reagents. Nitro compounds are also good precursors for various nitrogen derivatives such as nitriles, oximes, hydroxylamines, and imines. These transformations of nitro compounds are well established and are used routinely in organic synthesis. 

Fig. 4 PEGylation at the N-terminal methionine residue. The difference in pKa. between the N-terminal amine and other amines in the protein enables site-specific PEGylation. After reaction with aldehyde-terminated PEG at low pH, reduction of the resultant imine produces PEGylated protein...

Aldehydes and ketones can react with primary and secondary amines to form Schiff bases, a dehydration reaction yielding an imine (Reaction 45). However, Schiff base formation is a relatively labile, reversible interaction that is readily cleaved in aqueous solution by hydrolysis. The formation of Schiff bases is enhanced at alkaline pH values, but they are still not stable enough to use for crosslinking applications unless they are reduced by reductive amination (see below). 

In other studies, imine reduction by [Ir(cod)(PPh3)2]BF4 in THF has been shown to be first order in each of the catalyst, the H2, and the substrate. Initial formation of [IrH2(imine)2(PPh3)2]+ was proposed to lead to amine and [Ir(im-ine)2(PPh3)2], Oxidative addition regenerates the Ir(III) species [34]. 

Although imine hydrogenation is discussed in greater detail in Chapter 34, it seems appropriate at this point to describe one-pot reductive amination of aldehydes and ketones. The reductive amination of aldehydes and ketones using so-... 

The first example of this type of transformation was reported in 1974 [76]. Three catalysts were investigated, namely [Co2(CO)8], [Co(CO)g/PBu ], and [Rh6(CO)i6]. The [Co OJg/PBu ] catalyst showed activity for reductive animation using ammonia and aromatic amines. The [Rh6(CO)16] catalyst could be used for reductive animation using the more basic aliphatic amines that were found to poison the cobalt catalyst. This early report pointed out that the successful reductive animation of iso-butanal (Me2CCHO) with piperidine involves selective enamine hydrogenation, that reductive animation of cyclohexanone with isopropylamine probably involves imine hydrogenation, and that reductive amination of benzaldehyde with piperidine would presumably involve the reduction of a carbinolamine. 

Selectivities of about 2 1 are the best found for this type of hydrogenation and are highly dependent on the secondary amine used they seem to correlate with the nucleophilicity of the amine. Reductive amination of PhCHO with ben-zylamine can proceed through an imine intermediate, and thus gave better selectivities (12 1) but was found to be sluggish using this catalyst system. 

Generally, amine products can be obtained with 91-99% ee. It is noteworthy that the ee of the product does not correspond to the E Z ratio of the starting imines. Imines 103 and 104 exist as 2.5 1 and 1.8 1 (E)/(Z) isomers, but titanocene-catalyzed reduction produces amines with 93% and 97% ee, respectively.105... 

Secondary and tertiary amines can be obtained if the hydroformylation of olefins is conducted in the presence of primary and secondary amines under elevated hydrogen partial pressures. Here the rhodium catalyst is involved in both steps, the hydroformylation of an olefin as well as the hydrogenation of the imine or enamine resulting from a condensation of the oxo-aldehyde with the amine (Scheme 14). This combination of hydroformylation and reductive amination is also known as hydroaminomethylation and has been applied to the synthesis of various substrates of pharmaceutical interest [55-57] as well as to the synthesis of macrocycles [60-63] and dendrimers [64,65]. 

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