Aniline → 7-Bromodiethylfluorene-2-aldehyde

Participants

Reaction Steps

The convergent synthesis of AF-452-6OH (compound 9 in Scheme 1) was accomplished in two parallel sequences followed by a converging sequence: (i) a 4-step sequence to the protected 3-O-alkylated diphenylamine intermediate, (ii) a 3-step sequence to the tris(7-bromofluorene(triazine intermediate 7 and (ii) a 2-step sequence to AF-452-6OH (8). Briefly, the first sequence was started with tris-1,1,1-(hydroxymethyl)ethane, which was first protected as an acetonide derivative, i.e. 2,2,5-trimethyl-5-hydroxymethyl-1,3-dioxane (compound 1) in either reaction as indicated in Scheme 1, as reactions (i) or (ii). A Mitsunobu reaction of 1 with 3-bromophenol furnished the corresponding bromophenoxy-methyltrimethyl-1,3-dioxane (2) in 85% yield [Scheme 1, reaction (iii)]. The same compound could also be obtained in 59% yield from a copper-catalyzed reaction between 3-bromoiodobenzene and 1 [Scheme 1, reaction (iv)]. Compound 2 was aminated with aniline to produce the diphenylamine intermediate 3 [Scheme 1, reaction (v)]. In the second sequence, 2,7-dibromo-9,9-diethylfluorene (4) was first monoformylated to form 7-bromodiethylfluorene-2-aldehyde (5), which was then converted to the nitrile intermediate (6) in 93% yield [Scheme 1, reactions (vi) and (viii), respectively]. A less satisfactory conversion of the aldehyde intermediate 5 to the nitrile intermediate 6 via an hydroxyl-imine intermediate was also conducted [49% yield, Scheme 1, reaction (vii)]. The nitrile intermediate 6 was subsequently and catalytically trimerized in trifluoromethanesulfonic acid to afford the tribromo-1,3,5-triazine intermediate (7) in 95% yield [Scheme 1, reaction (ix)]. Covalently joining the triazine (7) component with the diphenylamine component (3) with the assistance of a Pd-catalyzed amination gave the precursor chromophore protected as an acetonide 8, [Scheme 1, reaction (x)]. Removal of the acetone protecting groups from 8 was accomplished by mixing and stirring 8 together with Dowex-50Wx2 (acid-form) resin, and the desired product, AF-452-6OH (9), was obtained in 90% yield [Scheme 1, reaction (xi)].

Provenance & Evidence