Synthetic Applications of Deamination Reactions

In conclusion, we propose a specific research program for deaminations in aqueous systems based on ideas mentioned in this section, namely to investigate (a) deamination kinetics and products of a series of simple aliphatic amines in water with sodium nitrite and perchloric acid at various acidities, (b) decompositions of diazenolates of the same amines in water and (c) decompositions of a standard type of N-nitroso amides, again of the same amines and all in the same aprotic solvent. The reaction conditions should be as similar as possible in the experiments of all three series. The series of amines should include methyl-, ethyl-, 1-methylethyl-, 1-methylpropyl-, and ( cr butyl)amine and [l- H]ethylamine, but not amines with longer aliphatic chains, as the very informative work of Southam and Whiting (1982) demonstrated clearly that, in deaminations of such amines, many mechanistically complex products are formed. In addition, micellar effects increase the complexity of reactions with such amines (see Sect. 7.3). It is obvious from the series of amines that we have proposed that this program is based on the work of Brosch and Kirmse (1991), Hovinen and Fishbein (1992), Hovinen et al. (1992), Finneman et al. (1993), and Ho and Fishbein (1994). Work with chiral 1-methylpropyl- and [l- H]ethyl-amine will provide information on the stereochemistry of these reactions. 

Investigations with N-nitroso amides and related N-nitroso compounds have the advantage that many difficulties with combined nitrosation and dediazoniation processes (as discussed above) can be avoided. Their results cannot, however, always be applied for an understanding and improvement of the most classical deamination method, i. e., the hydroxy-de-amination of an amine in an aqueous nitrosation. 

It has already been mentioned in Section 7.1 that, due to the formation of a series of highly reactive intermediate ions and complexes (ion pairs, etc.), a large number of products are formed in the majority of direct deaminations of alkylamines and deaminations via precursors. Therefore, deaminations do not display the same importance for syntheses as for mechanistic studies. 

There are very few exceptions. The most important are the methylation of alcoholic and carboxylic OH groups with diazomethane. This reaction is used for cases where high yields and mild conditions are required, e. g., for expensive hydroxy compounds like certain natural products. The methyl ester formation as well as the methylation of phenols does not need an acid catalyst as these substrates catalyze themselves the dediazoniation. For ether formation an acid catalyst, e. g., HBF4, is added (except from phenols). Typical is the methylation of 3)ff-hydroxycholestane, which proceeds in dichloromethane in 95 0 yield, as shown in the Organic Syntheses method of Neeman and Johnson (1973). Analogously, ethers can be transferred in dialkylmethyloxonium salts, as described in another Organic Syntheses procedure (Helmkamp and Pettitt, 1973) for the formation of a trimethyloxonium salt obtained 

Because of the toxicity and the relative instability of diazomethane, this methylation reagent has been replaced in recent years in many cases by (trimethylsilyl)diazo-methane. The latter is now commercially available as a 2 m solution in hexane (Aldrich). Aoyama and Shioiri (1990) described a general method for the methylation of alcohols in the presence of esters, ketones and CC double bonds. Methyl car-boxylates are quickly obtained from carboxylic acids with this reagent in the presence of methanol (Hashimoto et al., 1981 information from Aldrich, 1994). 

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Enzymatic hydroxylation of a carbon adjacent to an oxygen or nitrogen usually results in dealkylation by spontaneous hydrolysis of the initial hemiacetal or hemiaminal product. These conversions are commonly employed for two synthetic purposes cleavage of methyl ethers and oxidative deamination of amines. The latter is particularly useful in amino-add chemistry. These reactions can be catalyzed by P-450 monooxygenases or by flavin-containing monooxygenases (which are typically metal-free enzymes). As in the previous example, these hydroxylations require two dectrons that must be supplied by NADH or NAD PH, and most synthetic applications have rdied on whole miaobial cells rather than the isolated enzymes (Figure 1.7). 

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