Aryl alkyl ketones reductive amination

If combined with an alkaline or amine base (l-5equiv.) in MeOH under 10-50bar (1-5 x 10 hPa) of H2 and temperatures ranging from 25 to 50°C, all complexes catalyze the reduction of aryl alkyl ketones to the corresponding 1-arylalkanols. The role of the base was described by the authors as metal-assisted direct transfer of to the C=0 function , and higher rates were obtained... 

The strategy presented above with phenyl cyclohexyl ketone has been established to be general by investigating a number of aryl alkyl ketones and diaryl ketones [281,283]. The best cases of % ee are summarized in Schemes 14 and 15. 2-Ethoxybenzophenone 32 gives intramolecular cyclization product 33 as the only product in solution as well as within NaY. However, in NaY in the presence of chiral amines, intermolecular reduction product 34, in addition to 33, was obtained (Scheme 16). More importantly, with pseudoephedrine and (l/ ,2/ )-... 

Asymmetric reduction of ketones.1 Lithium aluminum hydride, after partial decomposition with 1 equiv. of 1 and an amine additive such as N-benzylmethylamine, can effect asymmetric reduction of prochiral ketones at temperatures of — 20°. The highest selectivity is observed with aryl alkyl ketones (55-87% ee), but dialkyl ketones can be reduced stereoselectively if the two groups are sterically different. Thus cyclohexyl methyl ketone can be reduced with 71% ee. 

In 2004 Alexakis independently reported on similar reaction conditions (Ti(OiPr)4/ Pd C/H2) as Nugent [22b, 23], albeit when using chiral amines, for example, phen ylethylamine (PEA), phenylpropylamine, and so on, to reductively aminate skeleton matching achiral ketones [30]. By doing so, he synthesized a set of five C2 symmet rical secondary amines from aryl alkyl ketones (Figure 7.5). The optimal conditions called for neat reaction conditions, equal molar quantities of the achiral ketone and chiral amine, Ti(OiPr)4 (3.0 equiv), Pd C (0.5 mol%), and 1.0 bar (14.5 psi) H2. No reaction times were reported. 

The outlined Nugent reductive amination protocol with (R) or (S) PEA and prochiral alkyl alkyl and aryl alkyl ketones (acydic or cyclic) allows higher yields and shorter reaction times than the previously practiced two step strategy via isolated (R) or (S) PEA, see Moss, N., Gauthier, J., and Ferland, J. M., (1995) Synlett, 142 144 ... 

The complexes of chiral amino-alcohols of type (13) with borane are reported to reduce aryl alkyl ketones to alcohols in optical yields up to 60% [for propiophenone reduction with (13 R = CHMe2)]/ whereas the asymmetric reduction of phenyl alkyl ketones with amine-boranes formed from chiral amines (such as 1-phenylethylamine or various L-a-amino-esters) has been found to give low optical yields of alcohols, i.e. up to 23%. ... 

Reductive amination (Section 22.10) Reaction of ammonia or an amine with an aldehyde or a ketone in the presence of a reducing agent is an effective method for the preparation of primary, secondary, or tertiary amines. The reducing agent may be either hydrogen in the presence of a metal catalyst or sodium cyanoborohy-dride. R, R, and R" may be either alkyl or aryl. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Moreover, reduction of alkyl aryl ketones can be used to access optically pure secondary aryl alkyl amines, as illustrated in an enantioselective synthesis of SDZ-ENA-713 (ll)60 and as we have demonstrated in a related process (Scheme 16.8). 

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