Synthesis of Unsymmetrical Aryl-Ethynylated Benzenes via Regiocontrolled Sonogashira Reaction of 1 , 3 , 5-Tribromobenzene

O acoplamento de Sonogashira do trimetilsililacetileno com 4-alcóxi-1-iodobenzenos resultou em 2-(4-(alquilóxi)fenil)etiniltrimetilsilanos, que sofrem desproteção pela retirada do grupo TMS usando fluoreto de tetrabutilamônio (TBAF) em THF à temperatura ambiente, resultando nos 2-(4-(alquilóxi)fenil)acetilenos terminais correspondentes. O acoplamento cruzado de Sonogashira do 1,3,5-tribromobenzeno com os arilacetilenos terminais em meio aquoso resultou na formação de derivados de benzeno mono-, die tri-alquinilados com rendimentos de moderados a bons. Os fatores que afetam a regiosseletividade da alquinilação também foram examinados.


Synthesis of unsymmetrical di-and tri-ethynylated benzenes
Next, cross-coupling of the mono-ethynylated dibromobenzene 5c with other terminal alkynes aiming to prepare unsymmetrical di-and tri-ethynylated benzenes  (10) in 60% yield as outlined in Scheme 2. The tri-ethynylated benzene product 10 was confirmed on the basis of its nuclear magnetic resonance ( 1 H and 13 C NMR) and mass spectra (MS) (see experimental section).

Conclusions
Three different 1-ethynyl-4-(alkyloxy)benzene candidates were prepared in three steps from 4-iodophenol.Then, these terminal acetylene candidates were employed in an efficient regiocontrolled Sonogashira cross-coupling with 1,3,5-tribromobenzene 4 for the preparation of unsymmetrical mono-, di-and tri-alkynylated benzene derivatives in moderate to good yields.Water/toluene mixed solvent was found to greatly enhance the crosscoupling reaction of 4-alkyloxyphenylacetylene with 1,3,5-tribromobenzene.These results encouraged us to Scheme 2. Regiocontrolled Sonogashira cross-coupling of compound 5c.conduct sequential Sonogashira followed by Susuki crosscoupling reactions on analogous candidates and the results are under progress.

Experimental
Melting points were determined in open glass capillaries with a Gallenkamp apparatus.The infrared (IR) spectra were recorded in potassium bromide disks on a Pye Unicam SP 3-300 and Shimaduz FTIR 8101 PC infrared spectrophotometer.NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer at 300 MHz ( 1 H NMR) and at 75 MHz ( 13 C NMR) using CDCl 3 as solvent and internal standard (d 7.27 and 77.36 ppm, for 1 H NMR and 13 C NMR, respectively).Chemical shifts (d) and J values are reported in ppm and Hz, respectively.Multiplicities are shown as the abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet).Electrospray ionization mass spectrometry (EI-MS) analyses were obtained at 70 eV with a Shimadzu GCMQP 1000 EX spectrometer.Analytical thin-layer chromatography (TLC) was performed using pre-coated silica gel 60778 plates (Fluka), and the spots were visualized with UV light at 254 nm.Fluka silica gel 60741 (70-230 mesh) was used for flash column chromatography.For the exclusion of atmospheric oxygen from the reaction medium, the aqueous solvent was firstly deoxygenated with a stream of argon for 30 min before use.1-Hexyloxy-4-iodobenzene (1a), 39,40 1-heptyloxy-4iodobenzene (1b), 39 and 1-octyloxy-4-iodobenzene (1c) 41 were prepared following literature procedures.

Synthesis of 1-ethynyl-4-(alkyloxy)benzenes 3a-c
To 2-(4-(alkyloxy)phenyl)ethynyltrimethylsilane 2a-c (0.5 mmol) in THF (3 mL), was added tetrabutylammonium fluoride (TBAF) (0.66 mL, 1 mmol) at room temperature.The resulting mixture was stirred for one hour at room temperature.The mixture was then filtered and the solvent was evaporated under reduced pressure to leave a crude oily product, which was purified by flash column chromatography using ethyl acetate-hexane (1:80) to furnish the corresponding desilylated products 3a-c in very good yields.

Synthesis of mono-and dialkynylated benzene derivatives
To PdCl 2 (PPh 3 ) 2 (7 mg, 0.01 mmol), CuI (3.8 mg, 0.02 mmol) in toluene (1 mL) and Et 3 N (140 mL, 2 mmol) in water (1 mL) were added 1,3,5-tribromobenzene 4 (315 mg, 1 mmol) and 4-alkoxyphenylethyne 3a-c (1 mmol) under an argon atmosphere.Stirring was continued for 24 h at 60 °C.Two phases of the resulting mixture were separated and the aqueous layer was extracted three times with diethyl ether (3 × 30 mL).The combined organic layer was concentrated under reduced pressure to leave a crude solid, which was purified by flash column chromatography using hexane/ ethyl acetate (20:1) to give the corresponding mono and dialkynylated products 5a-c and 6a-c.under argon atmosphere.The reaction mixture was stirred for 24 h at 60 °C.Two phases of the resulting mixture were separated and the aqueous layer was extracted three times with diethyl ether (3 × 30 mL).The combined extracts were evaporated under reduced pressure to leave a crude solid, which was purified by flash column chromatography on silica gel using hexane/ethyl acetate (10:1) to furnish 7 (40% yield) and 8 (4% yield).