LiAlH4, reaction with nitriles

Nitriles are common nitrogen-containing compounds. In Chapter 11 (Section 11.3.6), cyanide ion reacted as a nucleophile in an Sn2 reaction with alkyl halides to give a nitrile. When 2-bromohexane (22) is treated with NaCN in DMF, the product is 2-cyanohexane, 23. Reduction of this nitrile with LiAlH4 gives a primary amine, in this case l-amino-2-methylhexane 24. 

Nitriles are synthetically versatile functional groups because they are readily converted to carboxylic acids by hydrolysis under addic or basic conditions, reduced with LiAlH4 to form primary amines, and reaction with Grignard reagents leads to the formation of ketones. These reactions are illustrated here ... 

The yields of thietanone depend on the number of methyl groups attached to the 1,3-dihaloketones, a relationship attributed to the gem effect. Thus the unsubstituted thietane failed to form. Thietanes have been synthesized by a series of reactions involving addition of thiolacetic acid to a vinyl ketone, reduction with LiAlH4, substitution of the acyl group by the nitrile function, and subsequent ring closure to a cis-trans mixture of 119 (Eq. 11). 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

With few exceptions, organometalUcs add only once to nitriles (Section 8.6.4). Only if there is a very strong Lewis acid present to activate the anionic intermediate of the first nucleophilic attack will a second addition take place. An example of this second addition is the reduction of nitriles with LiAlH4, which proceeds all the way to the amine (Section 8.6.3). The AIH3 formed from the initial reduction acts as a Lewis acid to catalyze the second addition. This second addition can be prevented by using one equivalent of a less reactive aluminum hydride like LiAlH(OEt)3 or diisobutylaluminum hydride, [(CH3)2CHCH2l2AlH. The reactions in the acidic water workup are the reverse of imine formation (Section 10.5.2). 

Full details have appeared of the conversion of 3 -acetoxylanostan-7a-ol into the 32-oxime, and some derived products, via photolysis of the 7-nitrite (Barton reaction).Related compounds of the 8-en-ll-one series were obtained similarly. Attempts to hydrolyse the 32-nitrile (604) were unsuccessful, and reduction with LiAlH4 stopped at the intermediate stage, giving the 32-aldehyde (605) after hydrolysis. The aldehyde was readily reduced to the 32-alcohol, but could not be oxidized to the 32-carboxylic acid (606) even though several novel oxidation methods were devised, using pivalaldehyde as a model highly hindered aldehyde. 

Arylamines are prepared by nitration of an aromatic ring followed by reduction. Alkylamines are prepared by Sn2 reaction of ammonia or an amine with an alkyl halide as well as by a number of reductive methods, including LiAlH4 reduction of amides and nitriles. Also important is the reductive amination reaction in which an aldehyde or ketone is treated with an amine in the presence of a reducing agent. 

When sodium in ethanol is used as a reducing agent a minimum of 0.4 ml of nitrile should be worked up. The reaction is carried out in 10 ml of ethanol with the addition of 0.7 g of sodium cut into small pieces. When the reduction is complete (10—15 min) the reaction mixture is solidified, the solvent is distilled off, the solution is alkilized again, and the formed amine is steam distilled. The yields of this reaction are low. It is more advantageous to carry out the reduction with LiAlH4 in ether. 

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