Synthesis of ethynylated biaryls and asymmetric diethynylated benzene via sequential Sonogashira and Suzuki couplings in water

Two 1-bromo-4-ethynylbenzene candidates were synthesized from 1-bromo-4-iodobenzene via Sonogashira coupling then sequentially employed in Suzuki coupling with arylboronic acids in water to give ethynylated biaryl derivatives. Optimization of the reaction condition was done using two different palladium sources and various bases/solvents systems. Further sequential Sonogashira coupling of 1-bromo-4-ethynylbenzene candidates, in aqueous medium, afforded asymmetric diethynylated benzene derivatives.


Introduction
Palladium-catalyzed Sonogashira cross-coupling reaction of aryl halides with terminal alkynes is one of the most important reactions for synthesis of disubstituted alkynes. 1,20][11][12][13] Water as an available, cheap, renewable, safe and green solvent and allows easy work up and separation, has been exploited in several catalytic C-C bond formation reactions and was reported as an important partner in improving the catalyst activity. 14- 18In continuation of our research work on C-C cross-coupling reactions catalyzed by Pd(II)complexes in water, [19][20][21][22][23][24][25][26][27][28][29] we envisioned here that the 1-bromo-4-iodobenzene represents a suitable candidate for sequential Sonogashira and Suzuki cross-coupling for synthesis of new ethynylated biaryls and asymmetric diethynylated benzene derivatives using either the benzothiazole-oxime Pd(II)-complex I or the commercially available PdCl 2 (PPh 3 ) 2 II in aqueous medium.
Next, the coupling reaction was carried out using bis(triphenylphosphine)palladium(II) dichloride; PdCl 2 (PPh 3 ) 2 (cat II) in water or toluene at 60 °C using K 2 CO 3 or Et 3 N as bases and as shown in Table 1, runs 5-8.Conducting Suzuki coupling using Et 3 N/H 2 O/TBAB system in the presence of 1 mol% of cat II gave better result (93% yield) of 7 if compared with the catalytic system K 2 CO 3 /H 2 O/TBAB (70% yield) under the same conditions (Table 1, runs 5, 7).Toluene was not suitable solvent either in the presence of Et 3 N or K 2 CO 3 where the products yields were 20% and 30%, respectively (Table 1, runs 6 and 8).The obtained product was identical with that reported from Sonogashira coupling of phenylacetylene with 4-bromobiphenyl. 33 (9) was obtained in 60% yield after 24 hours at reflux (using Pd-cat I) and in 92% yield after 2 hr at 60 °C (using Pd-cat II), respectively.Product 9 was alternatively synthesized in literature by Sonogashira coupling of 4-bromophenyltrifluoroborate with phenylacetylene using Pd(PPh 3 ) 4 /CuI catalyst in DMSO-d 6 followed by Suzuki coupling of the product with 4bromotoluene. 34d-catalyst I was found to be less efficient (Table 2, run 5) in water/TBAB/K 2 CO 3 after heating the coupling partners 4 and 6d for 24 hr at reflux, where 2-(4-biphenylyl)-1-(3anisyl)acetylene (10) was obtained in 70% yield and the starting material did not completely consume as detected by TLC.In contrast, when PdCl 2 (PPh 3 ) 2 II was employed at 60 o C, the cross-coupling partners 4 and 6d were completely consumed after 2 hr with full conversion into the coupling product 10 and 95% isolated yield (Table 2, run 6).Structure of 2-(4-biphenylyl)-1-(3-anisyl)acetylene (10) was elucidated by 1 H and 13 C NMR and IR spectroscopy.The 1 H NMR spectrum of 10 revealed characteristic singlet signal at δ 3.87 due to methoxy protons in addition to the aromatic protons and its 13 C NMR spectrum showed 17 carbon signals and the IR spectrum showed a peak at 2206 cm -1 corresponding to the acetylene moiety.
The alkyne moiety is a π-electron donating group and consequently the aryl bromide 4 is considered as deactivated bromide.This may be a reason for, in some cases, the low conversion yields when our previously reported 22 Pd-catalyst I was employed in the catalytic system comparing to the more reactive catalyst PdCl 2 (PPh 3 ) 2 .a Conditions: Bromide/Boronic acid/Base/TBAB/water (ml): 1:1.5:2:0.6 :2, thermal heating.

Conclusions
We have developed an effective and convenient protocol for the palladium(II)-catalyzed ligandfree synthesis of 4-ethynylated biaryl derivatives via sequential Sonogashira then Suzuki crosscoupling reaction in water in the presence of K 2 CO 3 in open air.Also, sequential Sonogashira cross-coupling 1-bromo-4-iodobenzene different ethynylated benzene derivatives using ligandfree Pd(II)-catalyst, in aqueous medium under argon atmosphere, led to the formation of the asymmetric 1,4-diethynylated benzene derivatives.

Experimental section
General: Melting points were measured in open glass capillaries with a Gallenkamp apparatus.The infrared 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) at Cairo University or on a Jeol LA 400 MHz (400 MHz for 1 H, 100 MHz for the 13 C) at Assiut University, using CDCl 3 as solvent and internal standard (δ 7.27 and 77.36 ppm, for 1 H NMR and 13 C NMR, respectively).Chemical shifts (δ) and J values are reported in ppm and Hz, respectively.Electrospray ionization mass spectrometry (EI-MS) analyses were obtained at 70 eV with a type Shimadzu GCMQP 1000 EX spectrometer.Analytical thin-layer chromatography (TLC) was conducted 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 elimination of atmospheric oxygen from the reaction medium, the aqueous solvent was firstly deoxygenated with a stream of argon for 30 min before use.Synthesis of the Pd(II)-complex (Pd-cat I) 22 and 4-hexyloxyphenylacetylene 17 29,36 were prepared following the procedures reported in literature.