Activation of the Amine

The first examples were reported in a patent by Gresham et al. in 1950 [115]. NH3 reacts with propene in the presence of catalytic amounts of sodium in benzene at 950-1070 bar and 267-278°C to give mainly i-PrNH2 (Eq. 4.13). Under similar conditions (650-700 bar, 265°C), isobutene yields t-BuNH2. 

Using the above preformed catalysts, ethylene can be hydroaminated by primary and secondary amines under much lower pressures (3-55 atm) than those required for the reactions catalyzed by alkali metals (800-1200 atm). The example of N-ethyl-ation of piperidine has been described in full details in Organic Syntheses (Eq. 4.14) [120]. 

However, the use of higher olefins does not appear promising [119]. 

Lehmkuhl et al. demonstrated the beneficial effect of TMEDA (N,N,N, N -tetram-ethylethylenediamine) on the addition of n-BuNHj to ethylene catalyzed by n-BuNHIi (from n-BuNH2 and EtLi) [121]. This is also tme for secondary amines. The efficiency of this system is exemplified by the hydroamination of ethylene with EtjNH (Eq. 4.15). 

Using higher concentrations of the above EtjNli-TMEDA system allows operation under even milder conditions (6-10 bar, 70-90°C) [122]. However, the impor- 

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Rosenwald (19) attributed the acceleration of the reactions involved in inhibitor sweetening to the reaction of an unidentified oxidation product of the amine with thiol to produce mercaptyl radicals. However, the oxidation of neat DSBPD is slow at 20°C. (3.3 X 10"5 mole of 02 per mole of amine per second) and partial pre-oxidation of the DSBPD until 0.26 mole of 0> was absorbed per mole of amine did not enhance the activity of the amine (compare curves B and C in Figure 3). Furthermore, allowing the co-oxidation to proceed for a time before adding the... 

Monoalkylation of support-bound amines can also be realized by a three-step protocol involving initial protection/activation of the amine (e.g. as 2-nitrobenzenesulfon-amide [132,133], trifluoroacetamide [102], or 4,4 -dimethoxybenzhydrylamine [66]) followed by N-alkylation and deprotection. In particular, if monomethylations (see, e.g., Entry 7, Table 10.7) or allylations are to be performed, this three-step strategy will generally give the best results. 

Delayed-action catalysts have been made successfully. Buffered amine catalysts, where the activity of the amine has been reduced by the presence of an acid, have also been used. Acidic materials can be used to retard the urethane reaction. Hydrogen chloride and benzoyl chloride have been used in combination with amine-type catalysts to control reaction rates. A small percentage of acid can increase foaming time from 2.2 to 6 minutes (20). 

Scheme 1. Catalytic cycle for the hydroamination of olefins with activation of the amine by N-H deprotonation.

The catalytic activation of the amine via amide formation by oxidative addition to a low-valent transition metal has been performed by Milstein and co-workers [11]. Using the iridium(I) complex [Ir(PEt3)2(C2H4)2Cl] as an appropriate pre-catalyst in combination with 0.2 equivalents ZnCl2 as co-catalyst in THF, the addition of aniline to norbomene could be realized. By refluxing the reactants in the ratio Ir/ZnCl2/aniline/norbomene = 1 0.2 10 55 in THF for 48 h, 2-6 equivalents of xo-2-(phenylamino)norbomane as the reaction product could be generated catalytically. The catalytic reaction mechanism is shown in Scheme 5. 

The use of log +app values is appropriate for absorption rate constants but not for binding or equilibrium constants. In such cases, the biological activity parameters have to be corrected for the concentration of either the neutral or the ionized form, dependent on the species that interacts with the protein [75]. An investigation of the inhibition of monoaminoxidase by alcohols and amines shows that the amines (7=0) have much higher activities than the alcohols (7=1) and that the inhibitory activity of the amines decreases with increasing pH values. The corresponding QSAR equation (Eq. (41)) uses pifa/pH-corrected log 1 jKt values [59,60] ... 

The vapour pressures of solutions of lithium in mcthylamine have been determined from 218 to 278 K, The activity of the amine showed positive deviations from Raoult s law at low metal concentrations and negative deviation with increasing concentration as in metal-ammonia solutions. The system was considered to contain solvated metal atoms coexisting with free MeNH molecules. ... 

The aminolysis of esters catalyzed by complex 8 is possibly initiated by N-H activation of the amine by metal-ligand cooperation involving 8. Ester coordination followed by intramolecular nucleophilic attack by the amido ligand at the acyl functionality is thought to be a key step [15]. Overall, in one catalytic cycle, two... 

The Rh-catalyzed asymmetric isomerization of diethylgeranylamine to the enamine, which is a key step of the industrial synthesis of menthol, is similarly initiated by C— activation of the amine to form iminium-rhodium hydride rr-complex. ... 

More recently, Normant and coworkers have reported catalysis of the reaction between potassium acetate and benzyl chloride in acetonitrile by polyamines in a two phase system [28]. It seems likely that the catalytic activity reported by Normant et al. is related to the earlier alkylations discussed above. The authors state in their communication, however, their finding that ... quaternary ammonium salts corresponding to the diamines do not activate anions under the experimental conditions used. . In the reaction referred to here, it seems likely that the diamines are playing a dual role. The diamines are probably assisting in the solubilization of the solid (and relatively insoluble) potassium acetate by chelation of the potassium cation and the homogeneous reaction is then probably catalyzed by the quaternary ion formed in situ. That the catalytic activity of the amine depends on the hardness of the cation (the harder the cation, the less catalytic activity) [28] seems to accord with this interpretation although lattice energy differences cannot be discounted. 

Interfacial condensation with dicarbonyl chlorides could present the disadvantage of racemization due to nucleophilic displacement on the adjacent carbon, facilitated by the electronegative substituent, for this reason the activation of the amine by the phosphite procedure has been tried [53] following Scheme XXIII. 

The turnover of monoamines has been estimated by measuring the rate of decline of specific activity of the amines after introducing small amounts of radio-isotopic amines into the endogenous pools. This technique was first used to measure the rate of turnover of adrenal medullary catecholamines after the administration of radioactive precursors . The problem of the relative impenetrability of the blood-brain barrier to peripherally circulating amine was circumvented by the development of techniques for the administration of radioactive NE into the lateral cerebral ventricle , which allows a direct labelling of brain catecholamines. The principle of this approach is to introduce a "pulse dose" of labelled NE into the endogenous stores of this amine in the brain, and to follow the rate at which the radioactive material is catabolized and becomes diluted with newly S3mthesized NE1 9,132. Similar studies with H -5-HT have also been reported 3. 

On-resin methylation of the N terminus is based on selective mono-protection and activation of the amine, followed by methylation... 

Inspection of the curves in Fig. 18 reveals areas which can be attributed to the limiting catalytic current (with log i about —4.5). The reason for the relatively low value of the limiting catalytic current observed here may be variation in the catalytic activity of the amines employed, resulting from formation of complexes with anions. 

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