Aniline → 7-Bromodiethylfluorene-2-aldehyde

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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 a protected 3-O-alkylated diphenylamine intermediate 3, (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 (i) or reaction (ii), as indicated in Scheme 1. A Mitsunobu reaction of compound 1 with 3-bromophenol furnished the corresponding bromophenoxy-methyltrimethyl-1,3-dioxane 2 in 85% yield [Scheme 1, reaction (iii)]. The same compound 2 could also be obtained in 59% yield from a copper-catalyzed reaction (e.g., Ullmann ether synthesis) between 3-bromoiodobenzene and compound 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 a hydroxyl-imine intermediate was also conducted [49% yield, Scheme 1, reaction (vii)]. The nitrile intermediate 6 was subsequently and catalytically cyclotrimerized in trifluoromethanesulfonic acid to afford the tribromo-1,3,5-triazine intermediate 7 in 95% yield [Scheme 1, reaction (ix)]. Covalently joining the triazine component 7 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