Application of Hofmann Elimination in Linker Design

Acrylic acid was first attached to tlie hydroxy-modified solid support via an ester bond to yield 73. This was followed by a Michael addition to give the tertiary amine 74. Alkylation led to the quaternary ammonium salt 75, which is suitably predisposed for 3-eliniination induced by Huenig s base, thereby yielding the required tertiary amine. 

The system has tlie advantage that labihty of the ester linkage to the solid support is of no concern. No special entity has to be placed between the hydroxymethyl polystyrene and the acryl unit. The ester bond proved to be stable towards mildly basic and acidic conditions. 

Attachment of amine to resin 73 [83] Resin 73 (0.3 g, 0.17 mmol) was taken up in a mixture of DMF (4 mb) and the secondary amine (3 mmol) and shaken for 18 h at rt to yield 74. The resulting resin was then washed with DMF (three times), CH2CI2 (three times), and MeOH (twice), and dried under vacuum. For quaternization, the resin was suspended in a solution of the alkylating agent R X (1.5 mmol) in DMF (4 mb) and the mixture was shaken for 18 h at rt to yield 75. The resin was washed with DMF (three times), CH2CI2 (three times), and MeOH (twice) and dried under vacuum. 

Attachment of tryptamine to resin 76 was used as a starting point for the synthesis of a library of 800 structurally diverse tetrahydro-3-carbolines 78 (Fig. 7). The 

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