Aniline → 7-Bromodiethylfluorene-2-aldehyde

HRID 341114Notes

Reaction equation

HRID 341114 reaction equation
BrC1([O:12][C:13]2C=[CH:17][CH:16]=[CH:15][CH:14]=2)COC(C)(C)OC1(C)C.NC1C=CC=CC=1.C1(NC2C=CC=CC=2)C=CC=CC=1.[Br:39][C:40]1[CH:52]=[CH:51][C:50]2[C:49]3[C:44](=[CH:45][C:46](Br)=[CH:47][CH:48]=3)[C:43](CC)(CC)[C:42]=2[CH:41]=1>>[Br:39][C:40]1[CH:41]=[C:42]2[C:50]([C:49]3[CH:48]=[C:47]([CH2:46][CH3:45])[C:14]([CH:13]=[O:12])=[C:15]([CH2:16][CH3:17])[C:44]=3[CH2:43]2)=[CH:51][CH:52]=1

Participants

5

Reactant 4

HCID 6115AnilineHCID 11487DiphenylamineHCID 35310452,7-Dibromo-9,9-diethylfluoreneHCID 71029096Bromophenoxy-methyltrimethyl-1,3-dioxane

Product 1

HCID 867104607-Bromodiethylfluorene-2-aldehydeYield 93%

Procedure

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)].

Workup

  1. customto produce

Sources & evidence

ORD record
ord-45b7ef58966f4175a1e9b37175c48124
Source dataset
uspto-grants-2014_11
Patent number
US08895730B2

Reaction notes

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