Amination, by reduction of a ketone

Aluminum ethoxide, 21, 9 Aluminum isopropoxide, 21, 9 Amalgamated zinc, 20, 57 23, 86 Amide, 20, 37, 62, 66 preparation by ammonolysis, 20, 62 Amination, by reduction of a ketone in the presence of ammonia, 23, 68 of bromoacetal with use of high-pressure hydrogenation bomb, 24, 3 of a-bromoisocaproic acid, 21, 75 of a -bromo-/3-methylvaleric acid, 21, 62... 

Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

Metabolism is almost always an oxidative process. Reductive metabolism is much more limited. Functional groups that are reduced are, naturally, in a higher oxidation state. The more common examples include nitro groups, which are reduced to amines, and ketones, which reduce to alcohols. Chloramphenicol (8.28), an antibiotic that has fallen out of favor because of serious side effects, contains a nitro group that is reduced to the corresponding amine (8.29) (Scheme 8.9).7 Warfarin (Coumadin, 8.30), an anticlotting agent, is at least partially metabolized by reduction of its ketone to an alcohol. 

The presence of a chiral acetal, aminal or oxathiane in the vicinity of a carbonyl group can direct the reduction of a ketone toward a diastereoisomeric alcohol, whether or not chelation is operative. For example, the LiAlHf or Li 5-BU3BH reductions shown in Figure 6.13 give predominantly the diastereoisomer predicted by the Felkin-Ahn model while reductions with DIBAL or LiAlH4/MgBr2 give predominantly the diastereoisomer predicted by the chelation model [87,94, 213, 226],... 

More complex monosaccharides such as daunosamine and fucose are assembled using a similar strategy (Scheme 31).- - Cyclocondensation of diene (104) with acetaldehyde (9f) using the lanthanide catalyst Eu(hfc)3 gives the syn cycloadduct (105). Treatment of (105) with TFA followed by oxymercuration [Hg(OAc)2-NaCNBH4] and reductive amination of the oxime acetate (derived from the ketone) gives daunosamine (108). Fucose (107) is prepared from compound (106) by reduction of the ketone and treatment of the glycal with MCPBA in methanol. 

Metallic sodium. This metal is employed for the drying of ethers and of saturated and aromatic hydrocarbons. The bulk of the water should first be removed from the liquid or solution by a preliminary drying with anhydrous calcium chloride or magnesium sulphate. Sodium is most effective in the form of fine wire, which is forced directly into the liquid by means of a sodium press (see under Ether, Section II,47,i) a large surface is thus presented to the liquid. It cannot be used for any compound with which it reacts or which is affected by alkalis or is easily subject to reduction (due to the hydrogen evolved during the dehydration), viz., alcohols, acids, esters, organic halides, ketones, aldehydes, and some amines. 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

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. 

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). 

Addition of RMgBr to nitriles. Grignard reagents react with nitriles slowly if at all, but even r-butylmagnesium chloride will add to nitriles in refluxing THF when catalyzed by a copper(I) salt. The adduct can be converted to a ketimine by anhydrous protonation, to a primary amine by reduction (Li/NH,), or to a ketone by hydrolysis. The actual reagent may be a cuprate such as R3Cu(MgX)2. 

Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler-Clarke reductive alkylation of amines. 

Aqueous solutions of vanadous chloride (vanadium dichloride) are prepared by reduction of vanadium pentoxide with amalgamated zinc in hydrochloric acid [213], Reductions are carried out in solution in tetrahydrofuran at room temperature or under reflux. Vanadiiun dichloride reduces a-halo ketones to ketones [214], a-diketones to acyloins [215], quinones to hydroquinones [215], sulfoxides to sulfides [216] and azides to amines [217] (Procedure 40, p. 215). 

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]. 

By analogy with the enantioselective reduction of prochiral ketones to chiral alcohols an attractive method for producing enantiomerically pure amines would be enantioselective reductive amination of a ketone via enzymatic reduction of an imine intermediate (Scheme 6.11). Unfortunately the required enzymes-amine... 

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