Ketones dialkyl, reductive amination

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

The 36d-LAH complex was applied to the reduction of ketone oximes and their O-tetrahydropyranyl and O-methyl derivatives to optically active amines (69). Results for a variety of phenyl alkyl and dialkyl ketones are shown in Table 4. The predominant amines formed all were of the S absolute configuration with optical purities up to 56%. The oxime hydroxy group presumably reacts with the less hindered H2 in the 36d-LAH complex (cf. Scheme 6) to form an oxime complex (45), which probably undergoes infermolecular hydride transfert of H2 from a second molecule of the 36d-LAH complex (Scheme 8). Asymmetric reduction with the ethanol-modified 36d-LAH reagent gave amines of R con-... 

Chiral terf-diamines complexed with LAH gave very low optical yields in reductions of prochiral ketones. A/,/V,A/, /V -Tetramethyl-l,2-cyclohexanedi-amine complexed with LAH or LiAlD4 reduced phenyl alkyl, dialkyl ketones or benzaldehyde in <15% optical yields (109). 

Dialkyl ketones, especially sterically hindered ones, tend to give the corresponding alcohols to significant extents under conditions of reductive amination, resulting in lower yields of amines. As in the cases of the aromatic ketones described above, the addition of small amounts of acetic acid or ammonium acetate is effective to depress the formation of alcohols, which may become a significant side reaction over those catalysts that are active for the hydrogenation of ketones to alcohols such as ruthenium, Raney Co, and Raney Ni.17 Thus, the formation of 2-nonanol could be depressed effectively in the presence of ammonium acetate in the reductive amination of 2-nonanone over these catalysts (eq. 6.7). 

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. 

Primary and secondary aromatic amines can be alkylated by this same procedure, and the reaction can be controlled to result in mono- or dialkylation of primary amines. This amine alkylation is considered to involve reduction of the carboxylic acid to the aldehyde, formation of an iminium ion, and then reduction to the amine product. Actually, aldehydes or ketones can be used in place of a carboxylic acid. ... 

Asymmetric reductive amination of a dialkyl ketone by an alkylamine, catalysed by (193), formed the diazepane ring (194) with >97% yield and >94% ee. Purging of the by-product CO2 resulted in increased rate and almost quantitative yield of the product which otherwise formed carbamates with CO2 an adverse effect on the equilibrium between Ru-hydride and Ru-formate (catalyst forms) was thereby avoided. The rate could also be accelerated by trapping with nucleophilic secondary amines. ... 

Hydrogenation of an alkyl aldehyde or ketone in the presence of an alcohol can lead to a dialkyl ether (Scheme 23). In the presence of a primary or secondary amine or amide, the hydrogenation of alkyl ketones resulted in reductive amination. 

At almost the same time, MacMillan and coworkers found that the reductive amination starting from aldehyde, amine, and Hantzsch ester 39 also proceeded smoothly by means of 1 in the presence of 5 A MS to afford benzylic amines 43 with 83-97% ee (Scheme 11.11) [22]. They proved that dialkyl ketones as well as alkyl aryl ketones were suitable substrates even methyl ethyl ketone was reduc-tively aminated with 83% ee. They also reported the asymmetric reduction of pyruvic-acid-derived cyclic imino ester 44. In this reaction, the structure of 44 exhibited a remarkable correlation to MM3 calculations in terms of both hydrogen bond orientation and specific architectural elements that dictate iminium enan-tiofacial discrimination. 

The N,]S -dialkyl-/)-PDAs are manufactured by reductively alkylating -PDA with ketones. Alternatively, these compounds can be prepared from the ketone and -lutroaruline with catalytic hydrogenation. The /V-alkyl-/V-aryl- -PDAs are made by reductively alkylating -nitro-, -nitroso-, or /)-aminodipheny1 amine with ketones. The AijAT-dialkyl- PDAs are made by condensing various anilines with hydroquinone in the presence of an acid catalyst (see Amines-aromatic,phenylenediamines). 

The use of primary amines instead of ammonia affords l,2-dialkyl-/l -pyrrolines or l,2-dialkyl-/l -piperideines. Amino ketones with a primary amino group are intermediates in the reduction of y-nitropropylalkyl ketones (14,15) or S-nitrobutylalkyl ketones (16-18) by catalytic hydrogenation over Raney nickel or with zinc and hydrochloric acid (Scheme 1). 

The reductive alkylation of a primary amine with ketone leads to the formation of a stable imine. In the presence of hydrogen and a hydrogenation catalyst, the imine is reduced to a secondary amine. Similarly, a diamine reacts stepwise to form dialkylated secondary amines. However, several side reactions are possible for these reactions as outlined by Greenfield (12). The general scheme depicting the reaction between primary amine or diamine to yield secondary amine through a Schiff base is shown in Figure 17.1. 

The reductive alkylation of DAP with acetone led to high conversions and selectivity to the dialkylated product over Al, Bl, and BS2 catalysts. The ASl catalyst, which typically has lower activity than the Al or Pt-based catalysts showed greater formation of heterocycles. These results indicate that a more active catalyst, a shorter reaction time, a higher operating temperature, or sterically hindered amines/ketones will help minimize the formation of the heterocycles. Similar high selectivities were obtained with DAP-MIBK reaction over BSl and BS2 catalysts with no heterocycles being formed. However, over Al, the undesired heterocyclic compound was over 15%. This indicates that the reaction between diamines and ketones has a significant potential to form heterocyclic compounds unless the interaction between these is kept to a minimum by the use of a continuous flow reactor as proposed by Speranza et al. (16) or by other methods. 

The current work indicates that sulfided platinum catalysts are, in general, more active and selective than Pt, Pd, or sulfided Pd catalysts for reductive alkylation of primary amines with ketones. The choice of the catalyst preparation parameters, especially the support, plays a major role in determining the performance of the catalyst. Diamines, especially of lower molecular weight, tend to react with ketones even at room temperature to form heterocycles such as imidazolidine, diazepanes, and pyrimidines. Hence, a continuous reactor configuration that minimizes the contact between the amine and the ketone, along with a highly active catalyst is desired to obtain the dialkylated product. In general, sulfided Pt appears to be more suited for the reductive alkylation of ethylenediamine while unsulfided Pd or Pt may also be used if 1,3-diaminopropane is the amine. 

We developed a process of preparative and potential commercial utility for the production of tertiary aliphatic amines by the reductive alkylation of dialkyl amines and of alicyclic secondary amines with ketones in the presence of hydrogen and a catalyst3. Such tertiary amines have at least one secondary alkyl group. 

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

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