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 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 that a para-cyanophenyl ring was used on the right hand side of the molecule to avoid any possible unwanted side products)

A handful of important analogues of the reversed amide compounds have yet not been synthesized but can be prepared from mostly inexpensive reagents:

InChI=1S/C19H13F2N5O2/c20-19(21)28-14-8-6-12(7-9-14)17-25-24-16-11-22-10-15(26(16)17)23-18(27)13-4-2-1-3-5-13/h1-11,19H,(H,23,27) HHRGGCROWSDATP-UHFFFAOYSA-N FC(OC1=CC=C(C=C1)C1=NN=C2N1C(=CN=C2)NC(C2=CC=CC=C2)=O)F

InChI=1S/C19H12N6O/c20-10-13-6-8-14(9-7-13)18-24-23-17-12-21-11-16(25(17)18)22-19(26)15-4-2-1-3-5-15/h1-9,11-12H,(H,22,26) KVBLUVJYRHBFTE-UHFFFAOYSA-N C(#N)C1=CC=C(C=C1)C1=NN=C2N1C(=CN=C2)NC(C2=CC=CC=C2)=O

InChI=1S/C18H12F2N6O2/c19-18(20)28-13-5-3-11(4-6-13)16-25-24-15-10-22-9-14(26(15)16)23-17(27)12-2-1-7-21-8-12/h1-10,18H,(H,23,27) CJRKQMLRWDZHOR-UHFFFAOYSA-N FC(OC1=CC=C(C=C1)C1=NN=C2N1C(=CN=C2)NC(=O)C=2C=NC=CC2)F