Unsymmetrical amines

The above scheme to account for products of nitrile hydrogenation was proposed sixty years ago (80), and with minor variations 28,45,86] has withstood the test of time, It might be expected from the foregoing that, if a nitrile were reduced in the presence of an amine, unsymmetrical amines would result 48), and indeed the reaction provides an excellent way of preparing these amines 49,74). 

The A-Boc group also activates secondary acyclic amines toward deprotonation, and unsymmetrical amines may be deprotonated regioselectively in some instances. For example, selective deprotonation of a methyl proton over a methylene can be expected, as shown by the example in Scheme 30a. Similarly, regioselective removal of a cyclopropyl proton occurs in preference to a methylene, as shown in Scheme 30b. 

Unsymmetrical secondary and tertiary amines. Unsymmetrical amines are obtained in 50-95% yield by reaction of an alcohol and amine in the presence of this ruthenium catalyst. The intramolecular version of this reaction provides an efficient synthesis of cyclic amines either from oc,a>-amino alcohols and an alcohol or from a,tu-diols and an amine. The cyclization is useful for preparation of tetrahydroiso-quinolines.3... 

Scheme 39 Yet another mode of sequential unsymmetrical amination-Heck reactions [94,95]...

These studies indicate that the selectivity of a-aminoalkyl radical formation is Me > Et /-Pr, which is the opposite of that expected on the basis of radical stability. For example, in diisopropylmethylamine, methyl adducts are formed exclusively. Similar selectivity has been observed for oxidation of unsymmetrical amines by ferricyanide [43, 123] and in anodic processes [124]. This selectivity has been attributed to requirement of overlap between the half-vacant nitrogen p orbital and the a-CH orbital of the a-carbon. From the Newman projections below it can be seen that the conformation necessary for methyl deprotonation (a) is lower in energy than that for the isopropyl deprotonation (b) [5, 122]. 

In unsymmetrical amines this process generally leads to a-cyanation of the less substituted carbon. It was earlier proposed that the regioselectivity of cyanation was decided by the conformation of the amine adsorbed on the anode. However... 

Olofson and coworkers also introduced vinyl chloroformate as a reagent for the N-dealkylation of tertiary amines (Ref. 157,158,159). Compared with commonly utilized reagents in N-dealkylation procedures, the use of VOC-CI leads to significantly improved yields under milder conditions combined with greater discrimination between alkyl groups in unsymmetrical amines. The procedure is illustrated by the selective N-deethylation of N-ethyl piperidine to afford piperidine.HCI in 90% yield (Ref. 159) as depicted in scheme 107. 

It is reported in the early literature that unsymmetrical amine oxides or those of high molecular weight cannot be prepared by the action of ozone on the amine. This study shows that an unsymmetrical amine oxide, such as N-ethylpiperidine oxide, and a symmetrical high molecular weight amine oxide, such as tri-n-hexylamine oxide, can be prepared by ozonization in methanol solution. 

Unsymmetrical amines. Alcohols can be converted into unsymmetrical secondary and tertiary amines by treatment of the alkoxide (sodium hydride, DMF) with an amine and this phosphonium salt. 

Secondary and tertiary amines are commonly named as Afsubstituted primary amines. For unsymmetrical amines, the largest group is taken as the parent amine then the smaller group or groups bonded to nitrogen are named, and their location is indicated by the prefix N (indicating that they are bonded to nitrogen) ... 

The thermal decomposition of a quaternary ammonium hydroxide to alkene, tertiary amine and water was first observed by Hofmann in 1851 (equation 2) From his work with unsymmetrical amines. 

Scheme 1-150. Addition of a Grignard reagent onto an organic cyanide and subsequently of an organolithium onto the resulting A -metallo imine giving an unsymmetrical amine 207.

Hofmann elimination occurs in quaternary amines where one of the attached alkyl groups leaves the nitrogen in the form of an alkene. The reaction happens in an alkaline medium, usually with the aid of heating and vacuum. With unsymmetrical amines, the major alkene product is derived from the least substituted and generally the least stable alkyl group, an observation known as the Hofmann rule. This is in direct contrast to normal elimination reactions where the more substituted, stable product is dominant. 

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