Communications
the novel dithioester linker system (Scheme 2). After facile
removal of protecting groups like THP ethers (using pyridi-
nium p-toluenesulfonate (PPTS)) and TBDMS ethers (using
1m TBAF solution in THF), the resulting bromophenols 6
Scheme 3. Pd-catalyzed cross-coupling and fluorinating cleavage.
Yields of purified compounds over three steps.
Because high-loaded Merrifield resin can be used and
most of the transformations are quantitative, the method is
very suitable for the combinatorial synthesis of libraries with
trifluoromethylarenes. The advantage lies in the fluorination
in the final cleavage step, and therefore the negative influence
of the electronic structure of a CF3 substituent is circum-
vented. Based on the same principle the development of a
xanthogenate linker[7a] for the synthesis of trifluormethyl
ethers should be possible.
Experimental Section
Scheme 2. Modification of immobilized phenols and fluorinating cleav-
age: 1) a) dioxane/THF, RT, 12 h; b) RT, 4 h; c) THF, 708C, 24 h;
2) toluene, 808C, 16 h; 3) A: CH2Cl2, RT, 12 h; B: THF, 708C, 48 h; C:
THF, 708C, 24 h; 4) A,B,C: CH2Cl2, ꢀ78!08C, 3 h. Yields of purified
compounds over four steps.
3a: Representative synthesis for the immobilization of aryl halides
with elemental magnesium: A dry three-neck flask with a Dimroth
condenser and a dropping funnel was charded with magnesium
turnings (170 mg, 7.00 mmol, 7.00 equiv) suspended in anhydrous
THF (1.70 mL) under an argon atmosphere. The dropping funnel was
charged with a solution of 4-bromobiphenyl (1a; 1.67 g, 5.00 mmol,
5.00 equiv) in anhydrous THF. The reaction was started by continuous
addition of the solution to the suspension (when necessary three
drops of dibromoethane were added). The reaction mixture was
stirred for 1 h at 708C, then cooled to 408C and carbon disulfide
(1.90 g, 25.0 mmol, 25.0 equiv) was added. After 2 h of stirring at
408C, the red solution was transferred into a vial and Merrifield resin
(1.03 g, 1.00 mmol, 1.00 equiv) and potassium iodide (330 mg,
2.00 mmol, 2.00 equiv) were added. The vial was flushed with argon
and sealed, and the mixture was shaken overnight at 708C. The red
suspension was then transferred to a separation funnel, methylene
chloride (20 mL) was added, and the insoluble, inorganic compounds
were removed. Finally, the resin was filtered off, washed, and dried
under high vacuum to yield the red resin 3a (1.20 g; conversion:
95%).
were treated with different acid chlorides (Scheme 2, path A)
and isocyanates (Scheme 2, path B) to give the corresponding
esters and carbamates on bead, respectively. Cleavage from
the resins gave the trifluoromethylated compounds 7 and 8 in
yields up to 87% over four steps (based on the initial loading
of Merrifield resin).
Etherification under Mitsunobu conditions on bead
(Scheme 2, path C) followed by fluorinating cleavage gave
rise to trifluormethylated phenyl ethers 9 in very good yields
up to 79% over four steps. Notably, the crude products
already showed high purities (> 90%) and contained only
small amounts of succinimide as a byproduct, which could be
removed easily by flash filtration.
Importantly, formation of mono-Grignard reagents was
possible with dibromo- and diiodoarenes 10 (X = Br, I), giving
access to aryl halides resins 11 (Scheme 3). These underwent
coupling reactions to give biaryls with different aryl boronic
acids. Cleavage of the functionalized resins gave the trifluoro-
methylated biphenyls 12 in good yields of 41–47% over three
steps.
Palladium-catalyzed reactions on solid supports are
established and have already been demonstrated by a
number of Suzuki coupling reactions.[10] However, to our
knowledge, we describe herein the first Suzuki reactions with
retention of dithioester moieties in general.[11,12]
10a: Representative synthesis for the immobilization of func-
tionalized aryl halides using Knochelꢀs iPrMgCl·LiCl reagent. A
solution of iPrMgCl·LiCl (1.3m in THF; 6.50 mL, 5.00 mmol,
5.00 equiv) in a 9:1 mixture of anhydrous THF and dioxane (10 mL)
was stirred overnight in a Schlenk flask under an argon atmosphere.
The colorless precipitate was filtered off under argon and the filtrate
added dropwise to
a solution of 1,4-dibromobenzene (1.18 g,
5.00 mmol, 5.00 equiv) in THF. The mixture was stirred overnight at
ambient temperature, and carbon disulfide (2.28 g, 30.0 mmol,
20.0 equiv) was added. After 4 h of stirring at the same temperature,
the red solution was transferred into a vial and Merrifield resin
(1.03 g, 1.00 mmol, 1.00 equiv) and potassium iodide (320 mg,
2.00 mmol, 2.00 equiv) were added. The vial was flushed with argon
and sealed, and the mixture was shaken overnight at 708C. The red
suspension was then transferred to a separation funnel, methylene
chloride (20 mL) was added, and the insoluble, inorganic compounds
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11533 –11535