Ketones reductive animation

Reductive animation (Sections 24.6, 26.3) A method for preparing an amine by reaction of an aldehyde or ketone with ammonia and a reducing agent. 

Reductive Animation. An excellent application of organosilane reductions is found in the reductive animation of ketones. This method is a useful alternative... 

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

Turner has applied this deracemization process to a very interesting tandem transformation where y-amino ketones are transformed into enantiopure secondary amines via intramolecular reductive animation followed by deracemization (Scheme 5.41) [80]. 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive animation of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with /V-methyl maleimide or styrene (301). 

The final ring closure was attempted via several methods (O-activation, N-deprotection and intramolecular nucleophilic replacement, O-mesylation and subsequent hydrogenation, intramolecular Mitsunobu reaction), but all attempts were unsuccessful. The method implemented involved an intramolecular reductive animation. Compound 69 was oxidised with Dess-Martin periodinane to afford ketone 75, which was then hydrogenated in the presence of Pd/C, to give the desired ring-closed product (-)-indolizidine 167B. 

Reductive animation of a ketone with methylamine yields a secondary amine. Methamphetamine is /V-mcthyl-1 -phenyl-2-propanamine. 

One published synthesis of this amine 17 is by reductive animation.2 Note that it is not necessary, nor usually desirable, to isolate the rather unstable imine as reduction with NaB(CN)H3 or NaB(OAc)3H occurs under the conditions of imine formation.3 Since the imine is in equilibrium with the starting materials, slightly acidic conditions must be used so that the protonated imine is reduced more rapidly than the aldehyde or ketone. These two reducing agents are stable down to about pH 5. 

Racemic substituted aminoindanol 9 was synthesized in a 5-step sequence by nitration of 1-indanone, followed by ketone reduction and dehydration to give 6-nitro-l-indene and subsequent epoxidation of the olefin and final regioselective animation (Scheme 8.5). Optically pure (IR,2R)-and (1 S,2S)-6-nitro-1 -amino-2-indanol 9 were eventually obtained by resolution with mandelic... 

Imines are also intermediates in a useful process called reductive animation. In this reaction an aldehyde or a ketone is reacted with an amine to form an imine. A reducing agent, such as hydrogen and a catalyst, is also present in the reaction mixture. The reducing agent chosen is one that will not reduce the carbonyl compound but will reduce the more reactive imine. The imine is reduced as rapidly as it is formed and is not isolated. The reaction is illustrated in the following equation ... 

The synthesis is interesting because, after the acylation of the enamine, the amino group is introduced by a clever reductive animation with benzylamine (PI1CH2NH2) that forms the C-N bond, reduces the ketone, and hydrogenolyses the N-benzyl bond (Chapter 24). Dehydration and double alkylation then give tazadolene. 

The previous examples are selected asymmetric reductive animations of ketones to give chiral, a-branched amines (Eq. 32) however, the corresponding reactions of aldehydes are unknown. We reasoned that such a process might be realized if enolizable, a-branched aldehydes are used. Their asymmetric reductive amination should give -branched amines via an enantiomer-differentiating kinetic resolution (Eq. 33). 

Sodium cyanoborohydride, NaBHsCN Reacts with ketones and aldehydes in the presence of ammonia to yield an amine by a reductive animation process (Section 24.6). 

Reductive animation of carbonyl compounds.2 This reagent effects reductive ami-nation of aldehydes or ketones with amines (equation I). Yields tend to be only moderate with anilines, but are high with aliphatic amines. 

The conversion of prochiral centres in cyclic intermediates into fully blown chiral centres is a profitable way to transmit stereochemical information. The ant trail pheromone monomorine 42 when re-drawn so that we can see all three hydrogen atoms on the same surface of the molecule 42a, is an ideal candidate for synthesis by reductive animation. One of the three centres must be made asymetrically and then the other two set up by reduction of imines formed from that amine and two ketones as in 43. 

The most important reaction of imines is their reduction to form amines. The conversion of an aldehyde or ketone to an amine, via an imine, is known as reductive animation. This allows, for example, the selective formation of a secondary amine from a primary amine. 

Reductive animation of aldehydes or ketones by cyanoborohydride (or tnacetoxyborohydride)6 anion Selective reduction of carbonyls to alcohol, oximes to N alkylhydroxylammes, enamines to amines... 

In reductive animation, ketones or aldehydes react with amines in the presence of... 

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