Reductive amination of ketones

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). 

One route is by reductive amination of ketone (10) available by Friedel-Crafts reaction from acid (11) which we can make by an FGA strategy (Chapter T 24). 

In a different approach a super-high-throughput ee-assay was developed on the basis of chirally modified capillary array electrophoresis (CAE).90 CAE was used in the Human Genome Project, and commercially available instruments have been developed which comprise a high number of capillaries in parallel, for example the 96-capillary unit MegaBACE consisting of 6 bundles of 16 capillaries.91 The system can address a 96-well microtiter plate. It was adapted to perform ee-determinations of chiral amines, which are potentially accessible by catalytic reductive amination of ketones, transition metal catalyzed Markovnikov addition of ammonia, or enzymatic hydrolysis of acetamides (Scheme 14).90... 

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Ketimines are reduced to amines very easily by catalytic hydrogenation, by complex hydrides and by formic acid. They are intermediates in reductive amination of ketones (p. 134). An example of the reduction of a ketimine is conversion of 3-aminocarbonyl-2,3-diphenylazirine to the corresponding aziridine by sodium borohydride (yield 73%), by potassium borohydride (yield 71%) and by sodium bis (2-methoxyethoxy) aluminum hydride (yield 71%) [939]. 

Scheme 17 Reductive amination of ketones for the preparation of a-branched amines...

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

Reductive amination of ketones using p-anisidine and the Hantzsch ester for transfer hydrogenation is a low-yielding reaction in toluene at room temperature, but thiourea is an efficient catalyst, and yields of up to 94% are reported at 50 °C.334 A mechanism involving thiourea hydrogen bonding to the intermediate imine is supported by ab initio calculations. 

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... 

Wock-Hardt Ltd.54 reported a manufacturing process for the preparation of 2 (Scheme 8). In their approach, reductive amination of ketone 41 with dimethylamine hydrochloride using NaCNBH3 afforded amine 42 in 69% yield. The phenol was acylated with iV-ethyl-/V-methyl carbamoyl chloride (40) using KO/-Bu as the base instead of NaH to provide racemic carbamate 2 in 88% yield (98% pure by HPLC). Racemic 2 was further purified by making the oxalate salt, which provided 2 as a colorless crystalline oxalate salt in 100% purity. Resolution with DTTA followed by salt formation with tartaric acid afforded chiral tartrate salt 2. The overall yield of this process was 20%. 

Reductive amination of ketones and aldehydes is one of the best methods for synthesizing amines (Section 19-18). It also forms amino acids. When an a-ketoacid is treated with ammonia, the ketone reacts to form an imine. The imine is reduced to an amine by hydrogen and a palladium catalyst. Under these conditions, the carboxylic acid is not reduced. 

Inspired by the recent observation that imines are reduced with Hantzsch esters in the presence of achiral Lewis or Brpnsted acid catalysts (Itoh et al. 2004), we envisioned a catalytic cycle for the reductive amination of ketones which is initiated by protonation of the in situ generated ketimine 10 from a chiral Brdnsted acid catalyst (Scheme 13). The resulting iminium ion pair, which may be stabilized by hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine 11 could give an enantiomerically enriched amine 12 and pyridine 13. 

Scheme 14. Organocatalytic asymmetric reductive amination of ketones...

The reductive amination of ketones by the Leuckart method utilizes aimnonium formate both as the source of the nitrogen to form an imine while the formate acts as the reductant (Scheme 2.30b). 

Table 23. Reductive amination of ketones. Ketone Amine...

Reductive amination, the catalytic or chemical reduction of aldehydes (RCHO) and ketones (R2CO) in the presence of ammonia or an amine, accomplishes much the same purpose as the reaction of halides. It too can be used to prepare any class of amine, and has certain advantages over the halide reaction. The formation of mixtures is more readily controlled in reductive amination than in ammonolysis of halides. Reductive amination of ketones yields amines containing a ec-alkyl group these amines are difficult to prepare by ammonolysis because of the tendency of jec-alkyl halides to undergo elimination rather than substitution. 

Reductive amination of ketones yields amines containing a sec-a ky group such amines are difficult to obtain by ammonolysis because of the tendency for jec-alkyl halides to undergo elimination. For example, cyclohexanone is converted into cyclohexylamine in good yield, whereas ammonolysis of bromocyclohexane yields only cyclohexene. 

Reductive amination of ketones is accomplished in two steps. The borane complex is used to reduce RR C=N1 C1 which are formed by condensation of the ketones with ammonia in the presence of TiCl,-Ti(OPr )4. 

The amine 2 is made by a chemical reaction - the reductive amination of ketone 1. The starting material 1 and the reagents are all achiral so the product 2, though chiral, must be racemic. Reaction with one enantiomer of tartaric acid 3 forms the amine salt 4, or rather the amine salts 4a and 4b. Examine these structures carefully. The stereochemistry of tartaric acid 3 is the same for both salts but the stereochemistry of the amine 2 is different so these salts 4a and 4b are diastereoisomers. They have different physical properties the useful distinction, discovered by trial and error, is that 4b crystallises preferentially from a solution in methanol leaving 4a behind in solution. Neutralisation of 4b with NaOH gives the free amine (S) -2, insoluble in water and essentially optically pure. 

The reductive amination of ketones with a steroid structure makes possible the formation of an amino or substituted amino function on various carbon atoms of the steroid skeleton. In this case, different oxo functions are simultaneously present in the same steroid skeleton and selective reductive amination can frequently occur, because of the differences in steric hindrance of the carbonyl groups. Thus, the reductive amination of steroid derivatives often takes place with high stereoselectivity. The catalyst commonly used for the reductive amination is palladium on charcoal35 38. 

The strategies presented in Table 8.1 can be generalized in the following manner (1) carbanion addition to aldimine or ketimine derivatives (2) sequential amination-alkylation of aldehydes (carbanion addition to in situ formed aldimine derivatives) (3) transfer hydrogenation or hydrogenation of imines (4) reductive amination of ketones and (5) N-acetylenamide reduction. Because of the difficulty of their synthesis, a-alkyl,-alkyl substituted amines are highlighted whenever possible. 

Pienemann T, Sch er H-J (1987) Reductive amination of ketones and aldehydes at the mercury cathode. Synthesis 1987 1005-1007 Gomez JRO (1991) Electrosynthesis of N-methylhydroxylamine. J Appi Eiectrochem 21 331-334... 

Several examples of TH of imines have been reported using a range of complexes, most commonly based on precious metals including Ru, Ir and Rh [187, 188] Reduction aminations of ketones using ammonium formate with certain Cp /lr complexes have also been reported these are pH-dependent with respect to rate... 

Santoro E, Psaro R, Ravasio N et al (2012) Reductive amination of ketones or amination of alcohols over heterogeneous Cu catalysts matching the catalyst support with the iV-alkylating agent. ChemCatChem 4(9) 1249-1254... 

---