Sterically encumbered amines

Although complete replacement of chlorine atoms can be accomplished with most kinds of amines, this becomes difficult in the reactions with sterically hindered amines. Thus in the reactions of N3P3C16 with cyclohexylamine (71) and adamantyl amine (72), the yields of fully substituted products are low. In the reactions of N3P3C16 with further sterically encumbered amines such as... 

We first attempted to make the ammonium salts more stable using steric hindrance. We prepared a variety of sterically encumbered ammonium salts via the sequence shown in Equation 2. Although we could prepare a vau iety of hindered tertiary amines, successful quaternlzatlons were achieved only with methyl groups. These salts were more stable to phenoxlde than n-Bu NBr by factors of 10-50, demonstrating that steric hindrance can ay a significant part in stabilization of phase transfer catalysts. However, none of these salts were more effective than n-Bu NBr as phase transfer agents, probably due to their less lipophilic nature, and we turned our attention to other systems. 

Due to its wide application in peptide synthesis, 1-hydroxybenzotriazole 849 is the most commonly used benzo-triazole derivative with hundreds of references in Chemical Abstracts each year. The utility of 849 (Scheme 183) rests essentially on its readiness to form esters with carboxylic acids in the presence of dehydrating agents. l-Hydroxy-7-azabenzotriazole 847 is also used in peptide coupling reactions, especially with sterically encumbered amines. The faster reaction rates and reduced racemization is attributed to base catalysis by the adjacent pyridine nitrogen 848 during the coupling reactions. 

Aryl chlorides and heterocyclic aryl chlorides were converted into tertiary amines in high yields, employing [Pd(allyl)Cl]2 as the Pd source. Even electron-rich ortho-chloroanisole reacted with the sterically encumbered nitrogen nucleophiles in 65% yield. 

It will be recalled (Scheme 9.66) that reaction of ketones with secondary amines (such as azacylopentane [pyrrolidine]) produces enamines. Now, as shown in Scheme 9.88, when the unsymmetrically substituted ketone (2-methylcyclohexanone) forms an enamine, that specific enamine which is less sterically encumbered is favored and alkylation occurs on the previously unsubstituted side producing 2,6-dime thylcyclohexanone. 

A typical preparation protocol is shown in Scheme 2.146. In the first step in a one-pot reaction, 2,2 -[(l ,l )-hydrazine-l,2-diylidenebis(methanylylidene)] dibenzoic acid is reacted with 1,2-diphosphinobenzene and succinyl chloride to create the racemic bisdiazaphospholane with moderate yield. After condensation of all four carboxylic groups with an optically pure amine, diastereomeric amides are formed, which can be finally separated by liquid chromatography. By using phthaloyl chloride in the cyclization step or other enantiopure aryl amines, several analogs are accessible. For the linkage of sterically encumbering or less nucleophilic amines, the route via the corresponding acyl fluorides proved to be more successful [65]. 

Studies by Saveant and co-workers provide a more comprehensive picture of how steric and electronic effects govern the rates of aminium radical a-CH deprotonation. In this account, a combination of double potential step chronoamperometry, cyclic voltammetry, and laser flash photolysis methods were used to measure the rates of 9-CH deprotonation of aminium radicals 9, produced by SET oxidation of 9-substituted-N-methylacridanes (Scheme 8). Amines with differing base strength and steric constraints were employed as bases. The data (Table 101.3) clearly show that the deprotonation rate constants are significantly reduced when sterically encumbering substituents are present at C-9 of the acridanium... 

Much of the reactivity of amido ligands involves proton exchange processes that eliminate amine. The exchange is believed to occur by an associative mechanism consequently, the rate of reaction decreases for sterically congested metal complexes. For example, treatment of V[N(CH3)2]j with terf-butanol at room temperature forms V(O-f-Bu) in good yield, while at this temperature the more encumbered complex W[N(CH3)2] reacts only slowly with methanol and ethanol, and not at all with tert-butanoV° The use of bulky N-alkyl substituents allows for the isolation of low-coordinate complexes, such as Cr[N( -Pr)2]3- Amido complexes derived from primary amines can also serve as precursors to imido complexes. In many cases, amido halide complexes form imido complexes by loss of hydrogen chloride in the presence of a base (Equation 4.17). ... 

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