By Arylation of Support-Bound Amines

Few examples have been reported of the arylation of support-bound amines. Unlike alkylations, the arylation of a primary amine usually leads to a strong reduction of the nucleophilicity of the nitrogen atom, and so twofold arylation of resin-bound primary amines cannot be expected. Illustrative examples are listed in Table 

3 Preparation of Amines by Addition of Amines to C=C Double and C=C Triple Bonds 

Support-bound alkenes substituted with at least one electron-withdrawing group can react with primary or secondary amines (Table 10.6). If acrylates are used as Michael acceptors, the products (fl-alanine derivatives) are generally stable and do not undergo [l-elimination either upon N-acylation or upon treatment with TFA (for a longer synthetic sequence with a support-bound 2-(l-piperazinyl)propionate, see [42]). Suitable solvents for the addition of amines to electron-poor alkenes are THF, NMP, and DMSO. DMF is less suitable because it often contains dimethylamine, which also adds to Michael acceptors [112], 

Acrylic acid esterified with cross-linked hydroxymethyl polystyrene or Wang resin reacts smoothly with primary or secondary aliphatic amines at room temperature (Entries 1 and 2, Table 10.6). Only sterically demanding amines or amines of low nucleophilicity (anilines, a-amino acid esters) fail to add to polystyrene-bound acrylate. Support-bound acrylamides are less reactive than acrylic esters, and generally require heating to undergo addition with amines (Entries 4 and 5, Table 10.6). a, 3-Unsaturated esters with substituents in the 3-position (e.g. crotonates, Entry 3, Table 10.6) react significantly more slowly with nucleophiles than do acrylates. The examples in Table 10.6 also show that polystyrene-bound esters are rather stable towards aminolysis, and provide for robust attachment even in the presence of high concentrations of amines. Entry 10 in Table 10.6 is an example of the alkylation of a resin-bound amine with an electron-poor alkene to yield a fluorinated peptide mimetic. 

The addition of amines to electron-poor alkynes leads to the formation of enamines (Entry 11, Table 10.6). These acceptor-substituted enamines are more stable towards hydrolysis than enamines derived from unsubstituted ketones. Alkynes devoid of electron-withdrawing groups do not react smoothly with amines, and usually require Hg(II) catalysis to be converted to resin-bound enamines (Entry 12, Table 10.6). 

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