Synthesis of unsymmetrical aryl-ethynylated benzenes via regiocontrolled Sonogashira reaction of 1,3,5-tribromobenzene

ARTICLE

Synthesis of unsymmetrical aryl-ethynylated benzenes via regiocontrolled Sonogashira reaction of 1,3,5-tribromobenzene

Kamal M. Dawood^*; Hamdi M. Hassaneen; Hyam A. Abdelhadi; Mohamed S. M. Ahmed; Mohamed A.-M. Mohamed

Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt

ABSTRACT

Sonogashira coupling of trimethylsilylacetylene with 4-alkyloxy-1-iodobenzenes gave 2-(4-(alkyloxy)phenyl)ethynyltrimethylsilanes which undergo deprotection via removal of TMS-group using tetrabutylammonium fluoride (TBAF) in THF at room temperature to afford the corresponding terminal 2-(4-(alkyloxy)phenyl)acetylenes. Regiocontrolled Sonogashira cross-coupling of 1,3,5-tribromobenzene with the terminal arylacetylenes in aqueous medium resulted in the formation of mono-, di- and tri-alkynylated benzene derivatives in moderate to good yields. Factors affecting the regioselective alkynylation were also examined.

Keywords: arylacetylenes, cross-coupling, catalysis, palladium, aqueous media

RESUMO

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-, di- e tri-alquinilados com rendimentos de moderados a bons. Os fatores que afetam a regiosseletividade da alquinilação também foram examinados.

Introduction

Sonogashira cross-coupling, reaction of terminal alkynes with aryl halides in the presence of palladium(0)/copper(I) catalyst under basic conditions, has been established as one of the most convenient routes to symmetrical and unsymmetrical diarylethynes of potential biological and non-biological applications.^1-8 Synthesis of terminal arylacetylenes can be achieved through palladium-catalyzed Sonogashira coupling of aryl halides with mono-protected acetylenes followed by removal of the protecting group.^9,10 Furthermore, terminal arylacetylenes are involved in the construction of conjugated oligo- and polyarylacetylenes of wide range of industrial applications.^11-14 Polyhalogenated arenes were employed in Sonogashira coupling reactions with terminal alkynes.^15-24 In addition, aqueous organic solvents have been used for promotion of Sonogashira cross-coupling reactions in the presence of PdCl₂(PPh₃)₂.^25-29 In continuation of our research work on Sonogashira coupling reaction^27,30 we report in this work a regiocontrolled Sonogashira cross-coupling on 1,3,5-tribromobenzene as attractive strategy for synthesis of unsymmetrical ethynylated benzene derivatives. The effect of solvent/base ratios on the optimization of the regiocontrolled cross-coupling is evaluated.

Results and Discussion

At first, three different 4-alkyloxy-1-iodobenzene derivatives 1a-c were easily synthesized by reaction of 4-iodophenol with the appropriate alkyl bromides in dimethylsulfoxide (DMSO) in the presence of KOH at room temperature according to the reported Williamson method.³¹ Then, Sonogashira coupling of trimethylsilylacetylene with 4-alkyloxy-1-iodobenzene derivatives 1a-c using PdCl₂(PPh₃)₂ (1 mol%) and CuI (2 mol%) in water/toluene (2 mL, 1:1) in the presence of 2 equivalents of triethylamine (Et₃N) at room temperature for 24 h afforded 2-(4-(alkyloxy)phenyl)ethynyl-trimethylsilane 2a-c in 74, 86 and 96% yields, respectively (Scheme 1).

Next, removal of the trimethylsilyl (TMS) group from 2-(4-(alkyloxy)phenyl)-ethynyltrimethylsilanes 2a-c is achieved under mild conditions using tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF) following a related literature methodology.³² The deprotection process is completed within one hour at room temperature to afford the corresponding terminal arylacetylene products 3a-c in 74-85% yields. Further deprotection methods were reported using strong bases (such as NaH, NaOH, KOH, K₂CO₃ or t-BuOK) at high temperature.^33-38

Regio-controlled Sonogashira cross-coupling of 1,3,5-tribromobenzene 4 with 1-ethynyl-4-(alkyloxy)benzenes 3a-c

In the next part, the scope and limitations of the palladium-catalyzed regio-controlled Sonogashira cross-coupling reactions of 1,3,5-tribromobenzene 4 were investigated. Optimization of the reaction conditions for the regio-selective synthesis of mono-ethynylated dibromobenzene 5c from 1,3,5-tribromobenzene 4 was performed and the results are outlined in Table 1. Thus, firstly the cross-coupling reaction of 1,3,5-tribromobenzene 4 with 1-ethynyl-4-(octyloxy)benzene 3c in 1:1 molar ratio using PdCl₂(PPh₃)₂ (1 mol%) in the presence of CuI (2 mol%) using triethylamine (4 equiv.) was carried out in water/toluene (1:1, v/v) under argon atmosphere at 60 °C for 24 h till full conversion of 4 as examined by thin layer chromatography (TLC). After column chromatography, two products were isolated. The major product was obtained in 74% yield (Table 1, entry 1) and its structure was established as 1,3-dibromo-5-(2-(4-(octyloxy)phenyl)-ethynyl)-benzene 5c on the basis of its spectral analyses. The mass spectrum of 5c exhibited a peak at m/z 464 corresponding to its molecular ion and its ¹H and ¹³C nuclear magnetic resonance (NMR) spectra were in accordance with the assigned structure. The minor product was isolated in 20% and was confirmed as 1-bromo-3,5-di-(2-(4-(octyloxy)phenyl)-ethynyl)benzene 6c on the basis of its spectral analyses. Repeating the same reaction under similar conditions using three equiv. of Et₃N led to the formation of mono- and di-ethynylated bromobenzenes 5c and 6c in 80 and 12% isolated yields, respectively (Table 1, entry 2). Using two equiv. of Et₃N gave the desired products 5c and 6c in 90 and 8% isolated yields, respectively (Table 1, entry 3). The use of neat toluene as solvent under the optimized coupling conditions above employing 2 equiv. of Et₃N gave the products 5c and 6c in lower yields, 62 and 3% isolated yields, respectively (Table 1, entry 4). Similarly, performing the coupling reaction in degassed neat water under argon in the presence of 2 equiv. of Et₃N gave the products 5c and 6c in 70 and 5% isolated yields, respectively (Table 1, entry 5). Furthermore, the use of one equivalent of Et₃N in water/toluene (1:1, v/v) resulted in the formation 5c and 6c in 78 and 18%, respectively (Table 1, entry 6). Under the latter condition, coupling of 4 with 3c in toluene only afforded 5c and 6c in 45 and 9%, respectively (Table 1, entry 7). These results of entries 1-3 and 6, Table 1, are consistent with the reported ones declaring that aqueous organic solvents enhance Sonogashira cross-coupling reactions in the presence of PdCl₂(PPh₃)₂.^25-29 Accordingly, the selectivity towards mono-ethynylated dibromobenzene 5c reached its maximum when 2 equiv. of Et₃N and 1 equiv. of alkyne 3c were employed using a mixed reaction solvent; water/toluene (1:1, v/v).

Under the optimized conditions, regio-controlled Sonogashira cross-coupling reactions of further arylacetylenes 3a-b with 1,3,5-tribromobenzene 4 was achieved as depicted in Table 2. Thus, cross-coupling of 1,3,5-tribromobenzene 4 with 1-ethynyl-4-(hexyloxy)benzene 3a and with 1-ethynyl-4-(heptyloxy)benzene 3b were carried out in 1:1 molar ratio using PdCl₂(PPh₃)₂ in the presence of CuI in toluene/water mixed solvent and triethylamine as a base under argon atmosphere at 60 °C for 24 h resulted, in both cases, in full conversion into two products (major and minor) as depicted in Table 2. The reaction molar ratios were typically: 1 mmol arylacetylenes 3a-b, 1 mmol 1,3,5-tribromobenzene 4, 2 mmol Et₃N, 1 mol% PdCl₂(PPh₃)₂ and 2 mol% CuI in water/toluene (2 mL, 1:1 v/v). The major products were obtained in 94 and 93% yields, respectively (Table 2, entries 1 and 2) and their structures were established as 1-(3,5-dibromophenyl)-2-(4-hexyloxyphenyl)acetylene 5a and 1-(3,5-dibromophenyl)-2-(4-heptyloxyphenyl)acetylene 5b on the basis of their elemental and spectral analyses. The minor products were isolated in 2 and 4%, respectively (Table 2, entries 1 and 2), and were confirmed as 1-bromo-3,5-di-(2-(4-hexyloxyphenyl)-ethynyl)benzene 6a and 1-bromo-3,5-di-(2-(4-heptyloxyphenyl)ethynyl)benzene 6b on the basis of their spectral analyses (¹H, ¹³C NMR and mass spectra) as mentioned in the experimental section.

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 via two successive Sonogashira reactions is evaluated as shown in Scheme 2. Thus, Sonogashira cross-coupling reaction of 1,3-dibromo-5-(2-(4-(octyloxy)phenyl)ethynyl)-benzene 5c with 1-ethynyl-4-(heptyloxy)benzene 3b was performed applying the following reaction condition: 5c (1 mmol), 3b (1 mmol), PdCl₂(PPh₃)₂ (1 mol%), CuI (2 mol%) in toluene/water (2 mL, 1:1) using triethylamine (2 mmol) under argon atmosphere at 60 °C for 24 h to furnish two isolable products. After column chromatography, the obtained products were identified as 1-bromo-3-(2-(4-heptyloxyphenyl)ethynyl)-5-(2-(4-octyloxyphenyl)ethynyl)benzene (7) (40% yield) in addition to 1,3-di-(2-(4-heptyloxyphenyl)ethynyl)-5-(2-(4-octyloxyphenyl)ethynyl)-benzene (8) (4% yield), as shown in Scheme 2. Afterwards, the third regiocontrolled cross-coupling process for 1-bromo-3-(2-(4-heptyloxyphenyl)ethynyl)-5-(2-(4-octyloxyphenyl)ethynyl)benzene 7 was conducted via its reaction with 1-ethynylbenzene 9 in 1:1 molar ratio in the presence of PdCl₂(PPh₃)₂ (1 mol%), CuI (2 mol%) in toluene/water (2 mL, 1:1) using triethylamine (2 mmol) under argon at 60 °C for 24 h. This sequenced cross-coupling furnished the desired unsymmetrical tri-ethynylated benzene derivative; 1-(2-(4-(heptyloxy)phenyl)ethynyl)-3-(2-(4-(octyloxy)-phenyl)ethynyl)-5-(2-phenyl-ethynyl)-benzene (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 (¹H and ¹³C 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 cross-coupling reaction of 4-alkyloxyphenylacetylene with 1,3,5-tribromobenzene. These results encouraged us to conduct sequential Sonogashira followed by Susuki cross-coupling 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 (¹H NMR) and at 75 MHz (¹³C NMR) using CDCl₃ as solvent and internal standard (δ 7.27 and 77.36 ppm, for ¹H NMR and ¹³C NMR, respectively). Chemical shifts (δ) 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-4-iodobenzene (1b),³⁹ and 1-octyloxy-4-iodobenzene (1c)⁴¹ were prepared following literature procedures.

Synthesis of 4-(alkyloxy)phenylethynyltrimethylsilanes 2a-c

To a mixture of PdCl₂(PPh₃)₂ (14 mg, 0.02 mmol), CuI (7.6 mg, 0.04 mmol), and 1-alkyloxy-4-iodobenzenes 1a-c (2 mmol) in toluene (2 mL) was added trimethylsilylacetylene (0.34 mL, 2.4 mmol) at room temperature under an argon atmosphere. Triethylamine (0.28 mL, 4 mmol) in water (2 mL) was then added drop-wise and stirring was continued for 24 h at room temperature. The resulting two-phase mixture was separated and the aqueous layer was extracted with diethyl ether (3 × 30 mL). The combined organic layer was concentrated under reduced pressure to leave a crude solid, which was purified by chromatography on silica gel (hexane-ethyl acetate) to furnish the corresponding cross-coupled products 2a-c.

4-(Hexyloxy)phenylethynyltrimethylsilane (2a):⁴² this compound was purified by ethyl acetate-hexane (1:30) to yield 0.406 g of 2a (74%); ¹H NMR (300 MHz, CDCl₃) δ 0.24 (s, 9H) 0.91 (t, 3H, J 6.6 Hz), 1.26-1.45 (m, 6H), 1.74-1.80 (m, 2H), 3.95 (t, 2H, J 6.6 Hz), 6.81 (d, 2H, J 9.0 Hz), 7.39 (d, 2H, J 9.0 Hz).

4-(Heptyloxy)phenylethynyltrimethylsilane (2b):⁴³ this compound was purified by ethyl acetate-hexane (1:50) to yield 0.496 g of 2b (86%); ¹H NMR (300 MHz, CDCl₃) δ 0.24 (s, 9H), 0.91 (m, 3H), 1.28-1.46 (m, 8H), 1.76-1.81 (m, 2H), 3.95 (t, 2H, J 6.6 Hz), 6.81 (d, J 8.1 Hz, 2H), 7.39 (d, J 7.8 Hz, 2H).

4-(Octyloxy)phenylethynyltrimethylsilane (2c):^44,45 this compound was purified by ethyl acetate-hexane (1:70) to yield 0.58 g of 2c (96%); ¹H NMR (300 MHz, CDCl₃) δ 0.25 (s, 9H) 0.90 (m, 3H), 1.27-1.44 (m, 10H), 1.75-1.80 (m, 2H), 3.94 (t, 2H, J 6.6 Hz), 6.80 (d, 2H, J 8.7 Hz), 7.39 (d, 2H, J 9.0 Hz).

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.

1-Ethynyl-4-(hexyloxy)benzene (3a):⁴⁶ this compound was purified by ethyl acetate-hexane (1:80) to yield 155.5 mg (77%) as yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, 3H, J 7.2 Hz), 1.23-1.49 (m, 6H), 1.71-1.81 (m, 2H), 2.97 (s, 1H), 3.93 (t, 2H, J 6.6 Hz), 6.82 (d, 2H, J 9.0 Hz), 7.39 (d, 2H, J 9.0 Hz).

1-Ethynyl-4-(heptyloxy)benzene (3b):⁴⁷ this compound was purified by ethyl acetate-hexane (1:80) to furnish (162 mg, 75% yield), as yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, 3H, J 7.2 Hz), 1.26-1.45 (m, 8H), 1.73-1.80 (m, 2H), 2.94 (s, 1H), 3.91 (t, 2H, J 6.6 Hz), 6.83 (d, 2H, J 9.0 Hz), 7.38 (d, 2H, J 9.0 Hz).

1-Ethynyl-4-(octyloxy)benzene (3c):^41,45,48 this compound was purified by ethyl acetate-hexane (1:80) to give 184 mg (80% yield) as orange oil; ¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, 3H, J 7.2 Hz), 1.26-1.45 (m, 10H), 1.71-1.80 (m, 2H), 2.96 (s, 1H), 3.91 (t, 2H, J 6.6 Hz), 6.81 (d, 2H, J 9.0 Hz), 7.38 (d, 2H, J 9.0 Hz).

Synthesis of mono- and dialkynylated benzene derivatives

To PdCl₂(PPh₃)₂ (7 mg, 0.01 mmol), CuI (3.8 mg, 0.02 mmol) in toluene (1 mL) and Et₃N (140 µL, 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.

1,3-Dibromo-5-(2-(4-(hexyloxy)phenyl)ethynyl)benzene (5a): yield: 409.5 mg (94%) as white powder; m.p. 54-55 ºC; IR (KBr) υ_max/cm^-1 3065, 2926, 2210, 1550, 1464, 1243; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, 3H, J 5.6 Hz), 1.28-1.85 (m, 8H), 3.99 (t, 2H, J 6.6 Hz), 6.89-7.03 (m, 2H), 7.43-7.49 (m, 2H), 7.58 (s, 2H), 7.61 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.8, 26.1, 29.0, 31.8, 68.2, 85.3, 92.5, 114.1, 114.5, 122.7, 127.4, 132.9, 133.5, 133.8, 160.1; MS (EI, 70 eV) m/z 436 (M⁺, 37.6%), 352 (100%), 271 (3.44%), 192 (20.8%), 163 (32.7%), 87 (7.9%), 55 (15.5%); anal. calcd. for C₂₀H₂₀Br₂O: C, 55.07; H, 4.62%; found: C, 55.35; H, 4.79%.

1-Bromo-3,5-bis(2-(4-(hexyloxy)phenyl)ethynyl)benzene (6a): yield: 11 mg (2%) as white crystals; m.p. 108 ºC; IR (KBr) υ_max/cm^-1 3068, 2929, 2206, 1592, 1463, 1245; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, 6H, J 6.7 Hz), 1.28-1.83 (m, 16H), 3.99 (t, 4H, J 6.4 Hz), 6.87-6.95 (m, 4H), 7.44 (d, 4H, J 7.7 Hz), 7.47-7.58 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 23.1, 26.5, 28.5, 31.8, 68.4, 86.3, 91.7, 114.3, 114.8, 122.1, 132.4, 133.1, 133.6, 134.7, 159.7; MS (EI, 70 eV) m/z 557 (M⁺, 35.0%), 258 (4.0%), 250 (27.6%), 235 (59.4%), 205 (53.7%), 189 (95.1%), 179 (55.6%), 124 (59.1%), 93 (31.0%), 75 (27.7%), 53 (100%); anal. calcd. for C₃₄H₃₇BrO₂: C, 73.24; H, 6.69%; found: C, 73.13; H, 6.71%.

1,3-Dibromo-5-(2-(4-(heptyloxy)phenyl)ethynyl)benzene (5b): yield: 418.5 mg (93%) as white crystals; m.p. 96 ºC; IR (KBr) υ_max/cm^-1 3046, 2927, 2131, 1596, 1464, 1243; ¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, 3H, J 5.5 Hz), 1.28-1.84 (m, 10H), 3.97 (t, 2H, J 8.52 Hz), 6.90-7.15 (m, 2H), 7.43-7.47 (m, 2H), 7.58 (s, 2H), 7.61 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.5, 26.2, 28.7, 29.1, 31.9, 68.1, 85.2, 92.3, 114.0, 114.5, 122.5, 127.2, 132.8, 133.2, 133.6, 159.8; MS (EI, 70 eV) m/z 450 (M⁺, 3.8%), 433 (74.8%), 332 (29.6%), 234 (97.9%), 121 (100%), 93 (25.0%), 64 (47.2%), 56 (26.8%); anal. calcd. for C₂₁H₂₂Br₂O: C, 56.02; H, 4.93%; found: C, 56.29; H, 4.78%.

1-Bromo-3,5-bis(2-(4-(heptyloxy)phenyl)ethynyl)benzene (6b): yield: 23.4 mg (4%) as white powder; m.p. 55-56 ºC; IR (KBr) υ_max/cm^-1 3042, 2923, 2219, 1550, 1463, 1249; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, 6H, J 6.8 Hz), 1.28-1.83 (m, 20H), 3.99 (t, 4H, J 6.9 Hz), 6.88-6.97 (m, 4H), 7.44 (d, 4H, J 7.7 Hz), 7.47-7.54 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 14.2, 22.8, 26.2, 29.1, 29.6, 31.8, 68.1, 86.1, 91.2, 114.1, 114.4, 121.8, 132.4, 133.0, 133.3, 134.2, 159.4; MS (EI, 70 eV) m/z 585 (M⁺, 6.6%), 519 (6.9%), 457 (7.8%), 254 (9.0%), 80 (52.9%), 64 (73.7%), 57 (100%), 50 (18.8%); anal. calcd. for C₃₆H₁₄BrO₂: C, 73.83; H, 7.06%; found: C, 73.59; H, 7.15%.

1,3-Dibromo-5-(2-(4-(octyloxy)phenyl)ethynyl)benzene (5c): Yield: 417.5 mg (90%) as white powder; m.p. 58-59 ºC; IR (KBr) υ_max/cm^-1 3040, 2922, 2213, 1577, 1463, 1250; ¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, 3H, J 5.4 Hz), 1.28-1.85 (m, 12H), 3.98 (t, 2H, J 6.5 Hz), 6.85-6.91 (m, 2H), 7.42-7.47 (m, 2H), 7.58 (s, 2H), 7.61 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.6, 26.0, 29.1, 29.2, 29.3, 31.8, 68.1, 85.2, 92.3, 113.9, 114.6, 122.6, 127.2, 132.7, 133.2, 133.4,159.8; MS (EI, 70 eV) m/z 464 (M⁺, 29.4%), 352 (100%), 350 (54.7%), 192 (23.3%), 163 (37.4%), 71 (13.9%), 57 (44.4%), 55 (28.9%); anal. calcd. for C₂₂H₂₄Br₂O: C, 56.92; H, 5.21%; found: C, 56.85; H, 5.09%.

1-Bromo-3,5-bis(2-(4-(octyloxy)phenyl)ethynyl)benzene (6c): yield: 49 mg (8%) as white crystals; m.p. 63 ºC; IR (KBr) υ_max/cm^-1 3042, 2923, 2205, 1589, 1464, 1247; ¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, 6H, J 6.6 Hz), 1.28-1.83 (m, 24H), 3.99 (t, 4H, J 6.5 Hz), 6.83-6.89 (m, 4H), 7.44 (d, 4H, J 7.8 Hz), 7.47-7.58 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.6, 26.0, 29.1, 29.2, 29.3, 31.8, 68.1, 86.0, 91.4, 114.3, 114.6, 121.8, 132.7, 133.1, 133.3, 133.9, 159.7; MS (EI, 70 eV) m/z 614 (M⁺, 39.2%), 502 (12.5%), 390 (67.7%), 250 (10.9%), 71 (56.7%), 57 (100%), 55 (57.1%); anal. calcd. for C₃₈H₄₅BrO₂: C, 74.37; H, 7.39%; found: C, 74.05; H, 7.19%.

Synthesis of 1-(2-(3-bromo-5-(2-(4-(octyloxy)phenyl)ethynyl)phenyl)ethynyl)-4-(heptyloxy)-benzene (7)

To PdCl₂(PPh₃)₂ (7 mg, 0.01 mmol), CuI (3.8 mg, 0.02 mmol) in toluene (1 mL) and Et₃N (140 µL, 2 mmol) in water (1 mL) were added 1-(2-(3,5-dibromophenyl)ethynyl)-4-(octyloxy)benzene 5c (464.2 mg, 1 mmol) and 1-ethynyl-4-(heptyloxy)benzene 3b (216 mg, 1 mmol) 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).

1-Bromo-3-(2-(4-(heptyloxy)phenyl)ethynyl)-5-(2-(4-(octyloxy)phenyl)ethynyl)benzene (7): yield: 239.5 mg (40%) as white powder; m.p. 56-57 ºC; IR (KBr) υ_max/cm^-1 3096, 2926, 2205, 1595, 1464, 1246; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, 6H, J 4.3 Hz), 1.28-1.82 (m, 22H), 3.95-4.00 (m, 4H), 6.83-6.89 (m, 4H), 7.42-7.44 (m, 4H), 7.45-7.46 (m, 2H), 7.58 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.6, 22.7, 25.9, 29.0, 29.15, 29.18, 29.2, 29.3, 29.7, 31.7, 68.1, 68.2, 81.9, 85.9, 87.9, 91.4, 114.5, 114.6, 121.8, 125.7, 125.8, 125.9, 132.7, 132.8, 133.9, 158.9, 159.7; MS (EI, 70 eV) m/z 599 (M⁺, 17.0%), 598 (40.9%), 586 (24.7%), 390 (100%), 250 (18.9%), 96 (11.9%), 71 (20.9%); anal. calcd. for C₃₇H₄₃BrO₂: C, 74.11; H, 7.23%; found: C, 73.85; H, 7.09%.

1,3-Bis(2-(4-(heptyloxy)phenyl)ethynyl)-5-(2-(4-(octyloxy)phenyl)ethynyl)benzene (8): yield: 29 mg (4%) as yellow oil; IR (KBr) υ_max/cm^-1 3048, 2925, 2208, 1602, 1465, 1247; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (m, 9H), 1.28-1.80 (m, 32H), 3.96-4.01 (m, 6H), 6.87-6.90 (m, 6H), 7.44-7.47 (m, 6H), 7.59 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 14.0, 22.6, 25.9, 29.0, 29.2, 29.7, 31.7, 68.2, 86.7, 90.5, 114.7, 124.3, 133.1, 133.4, 159.5; MS (EI, 70 eV) m/z 735 (M⁺, 17.0%), 718 (15.9%), 575 (19.5%), 486 (24.5%), 462 (36.7%), 410 (24.5%), 351 (23.6%), 220 (43.7%), 107 (74.5%), 82 (100%), 65 (34.7%), 50 (13.5%); anal. calcd. for C₅₂H₆₂O₃: C, 84.97; H, 8.50%; found: C, 84.85; H, 8.48%.

Synthesis of 1-(2-(4-(heptyloxy)phenyl)ethynyl)-3-(2-(4-(octyloxy)-phenyl)ethynyl)-5-(2-phenylethynyl)benzene (10)

To a mixture of 1-(2-(3-bromo-5-(2-(4-(octyloxy)phenyl)-ethynyl)phenyl)ethynyl)-4-(heptyloxy)benzene (7) (599 mg, 1 mmol) and phenylethyne (9) (90 µL, 1 mmol), in toluene (1 mL) and water (1 mL), was added Et₃N (140 µL, 2 mmol) followed by adding PdCl₂(PPh₃)₂ (7 mg, 0.01 mmol) then CuI (3.8 mg, 0.02 mmol) 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 give compound 10 in 372.5 mg (60% yield) as yellow oil. IR (KBr) υ_max/cm^-1 3046, 2922, 2205, 1573, 1464, 1246; ¹H NMR (300 MHz, CDCl₃) δ 0.91-0.94 (m, 6H), 1.30-1.84 (m, 22H), 3.99 (t, 4H, J 6.4 Hz), 6.90 (d, 4H, J 6.7 Hz), 7.37-7.39 (m, 3H), 7.49 (d, 4H, J 5.7 Hz), 7.56 (d, 2H, J 3.9 Hz), 7.63 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 14.1, 22.6, 22.6, 25.9, 26.0, 29.0, 29.1, 29.2, 29.3, 29.6, 29.7, 31.7, 31.8, 68.1, 86.6, 88.0, 90.3, 90.7, 114.5, 114.6, 122.9, 123.9, 124.4, 128.3, 128.5, 131.7, 132.8, 133.1, 133.5, 133.7, 159.5; MS (EI, 70 eV) m/z 621 (M⁺, 22.5%), 598 (0.4%), 430 (29.9%), 406 (36.3%), 234 (51.2%), 210 (100%), 181 (18.2%), 57 (70.3%), 55 (20.6%); anal. calcd. for C₄₅H₄₈O₂: C, 87.05; H, 7.79%; found: C, 86.87; H, 7.68%.

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.

Acknowledgments

The authors are greatly indebted to Faculty of Science, Cairo University for the financial support.

Submitted: February 28, 2014

Published online: July 15, 2014

Supplementary Information

The supplementary material is available in pdf: [Supplementary material]

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Publication Dates

• Publication in this collection
  30 Sept 2014
• Date of issue
  Sept 2014

History

• Received
  28 Feb 2014
• Accepted
  15 July 2014