Synthesis of the Reverse Amide Linked Series

Para-chlorophenyl core

The Reversed Amide has been discussed previously in issue #301, #352 and #358. The initial approach of synthesising and reducing the azide to the amine worked only on a small scale (Experiments CCS-3-2 and CCS-4-1). When upscaling this, the iminophosphorane was obtained rather than the amine. Basic methods of hydrolysis of the iminophosphorane failed to force the reaction to completion (Experiment CCS-5-1). However, hydrolysis could be forced using acidic conditions, although with slow reaction times (Experiment NA-7-2). This provided a pure amine product; therefore, was a favoured method over catalytic hydrogenation or borohydride reduction of the azide, where yields were low and isolation of product difficult (Experiments BM-5-1 / NA-2-1 and NA-2-4).

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The amine however, proved to be unreactive with standard coupling conditions (Experiments CCS-6-1, NA-3-1, NA-3-2, FG-5-1, FG-5-2, FG-5-3, FG-5-4). Also, an attempt to produce the urea also did not result in any reaction and only starting material remained (Experiment VD-4-1).

Para-cyanophenyl core

A para-cyanophenyl core was used to avoid any competition with a metal catalysed substitution at that position, compared to the chloride on the pyrazole ring. (Experiments JH-5-1, JH-5-2 and JH-7-1). OSM-W-6 and OSM-W-7 will be sent for testing.

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