Synthesis of the Reverse Amide Linked Series
The Reversed Amide (discussed: #301, #352, #358 has been synthesised as described here.
The initial approach of synthesising and reducing the azide to the amine worked only on a small scale (CCS-3-2, CCS-4-1). When upscaling this (TL-4-2, TL-4-3), the iminophosphorane was obtained rather than the amine. Basic methods of hydrolysis of the iminophosphorane failed to force the reaction to completion (CCS-5-1). However, hydrolysis could be forced using acidic conditions, although with long reaction times (NA-7-2). This provided pure amine product (OSM-W-2) and was therefore favoured over alternative methods involving catalytic hydrogenation or borohydride reduction of the azide, where yields were low and isolation of product was difficult (BM-5-1, NA-2-1, NA-2-4).
The amine (OSM-W-2) proved to be unreactive to carboxylic acids under standard coupling conditions (CCS-6-1, NA-3-1, NA-3-2, FG-5-1, FG-5-2, FG-5-3, FG-5-4). An attempt to produce the urea also did not result in any reaction and only starting material remained (VD-4-1).
An alternative synthetic route was successfully executed via a Buchwald–Hartwig amination of the chloro-substituted triazolopyrazine core to give OSM-W-6 and OSM-W-7 (JH-5-1, JH-5-2, JH-7-1). (Note a para-cyanophenyl ring was used (instead of para-chloro) in these reactions to avoid any possible unwanted side products).
