Deamination of alicyclic amines

As discussed in Section 7.4, conformational control in deamination of open-chain amines is difficult to evaluate because the activation energies of conformational changes are often smaller than those of the steps in deamination reactions. Alicyclic amines are more suitable for such mechanistic investigations. In addition, the con-formers of such amines can be locked if they contain bulky substituents (tert-hvXyX) or if the amines are based on bi- and polycyclic hydrocarbons (decalinamines, cholestaneamines, norbornylamines, etc.). We shall therefore concentrate first on the deamination of the epimeric 4-( er butyl)cyclohexylamines. Then, we will discuss the structural problems of cyclic carbocations formed in deamination of norbor-nylamine, cyclopropylmethylamine, and cyclobutylamine, i. e., compounds that are at the center of interest in the debate on classical versus nonclassical carbocations. 

The most extensive investigation on the deamination of trans- and cis-4- tert-butyl)cyclohexylamine (7.89 and 7.90, respectively) by the three procedures mentioned was conducted by Whiting s group (Maskill et al., 1965 Maskill and Whiting, 1976) in acetic acid (in part in butyric acid). 

The amount of work involved in the deamination of ten different starting materials becomes evident from the fact that a total of 17 and 12 products was detected and analyzed for the experiments in the trans- and the cw-series, respectively. The corresponding tables contain 116 analyses The products are cycloalkenes (from elimination), acetates and butyrates from external substitution, and products of internal substitution (ArNH, AcO, OH, depending on the procedure used). Two isolated products, obtained in 0.3-0.5% and 2.5% yield, were identified later by Whiting s group (Cooper et al., 1982), as cis- and m 5-3-butylcyclopentylmethyl esters, i. e., products of ring contraction. 

Maskill and Whiting s investigation is of general interest it allows comparison of yields in the ten reactions. Dediazoniation via triazenes (7.91 and 7.92) gives very good yields 93-99% (cis) and 77-85% (trans) via nitroso amides (7.93 and 7.94) 55 % (cis) and 75-84% (trans) are reported. Direct deamination yields are low, as expected (18% for cis, 14% for trans). Nevertheless, it is interesting to note that the yields in ra-deamination can be doubled (37%) when the reaction is conducted under nitrogen.  

Comparison of product distributions from cis- and m 5-precursors demonstrates clearly that there are practically no feasible common intermediates that allow a crossover between the two series. This is best shown from the total extent of hydride shift, which is very low for all six experiments with trans-simine and its derivatives (1.3 to 2.2%), but high in the cw-series ( 26% to 34% 14% for direct deamination). 4-( e Butyl)cyclohex-l-ene is an elimination product formed in relatively small amount (7.6-17%) from trans-compounds, but it is by far the dominant product in the cw-series (70-78%). In external substitution by acetate this result is reversed. Internal substitution accounts for 15.1-44% of products with the trans- 

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Deamination of primary amines to rearranged alcohols (via diazonhjm compounds) with ring contraction or enlargement for alicyclic amines... 

Deamination of primary amines by diazotization to give rearranged alcohols. In the case of alicyclic amines, ring enlargement or contraction occurs ... 

As outlined in section I.D, there is no compelling evidence for non-classical intermediates in the deamination of acyclic amines, but a series of tracer and stereochemical studies have led many workers to postulate their existence in the alicyclic field In forming... 

Our understanding of the deamination of primary aliphatic amines by the action of nitrous acid has gained much from studies of alicyclic compounds, including Shoppee s extensive work in the steroid field. 

Many oxidative processes (e.g., benzylic, allylic, alicyclic, or aliphatic hydroxylation) generate alcohol or carbinol metabolites as intermediate products. If not conjugated, these alcohol products are further oxidized to aldehydes (if primary alcohols) or to ketones (if secondary alcohols). Aldehyde metabolites resulting from oxidation of primary alcohols or from oxidative deamination of primary aliphatic amines often undergo facile oxidation to generate polar carboxylic acid derivatives." As a general rale, primary alcoholic groups and aldehyde functionalities are quite vulnera-... 

Epoxides may be cleaved by amines. This reaction is used in the synthesis of aminoalcohols (53) studied as potential adrenergic drugs (Scheme 21). The amine cleavage of the epoxide and the subsequent nitrous acid deamination of the aminoalcohol are used for the ring enlargement of alicyclic ketones (TiffeneauDemjanov reaction). By this sequence of reactions, for example, cycloheptanone (54) may be converted to cydooctanone (55) (Scheme 21). 

A number of features in deamination have their counterparts in solvolytic El reactions. Transannular 1,5 and 1.6 shifts have been observed in deaminations of eight- to twelve-membered alicyclic amines, viz. 

Path (a) elimination and hydrocarbon formation. Olefins are usually formed in deamination reactions. With alicyclic amines, it has often been observed that axial amines yield far larger amounts of olefins than equatorial amines The ranr-coplanar arrangement of the... 

Reductive C-N bond cleavage has been demonstrated in more complex systems using ethyl chloroformate as a solvent. Chlorination of corticosteroid cyclic ethers has been observed. Tertiary aliphatic and alicyclic amines can be dealkylated. Phenyl chloroformate, however, is usually regarded as the reagent of choice. In summary, deamination, demethylation, debenzylation, and deal-lylation of tertiary amines can all occur on treatment with ethyl chloroformate but the regioselectivities of these reactions are difficult to predict. ... 

The spontaneous decomposition of the diazonium ions obtained on treating non-aromatic primary amines with nitrous acid in weakly acidic solutions (deamination reaction) is an irreversible reaction possessing great driving force under mild conditions. The steric consequences of the reaction in the aliphatic and alicyclic fields have proved to be quite diverse, "... 

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