Synthesis of cyclic phenyl hexayne from Me 3 Si-/Ph 2 P(O)-protected ethynes

Abstract

A practical approach for the synthesis of cyclic phenyl hexayne is demonstrated through a one-pot deprotection/transformation of magnesium acetylide into a copper acetylide/Sonogashira coupling procedure, followed by dephosphination, Hay coupling, desilylation, and Eglinton coupling. This approach avoids tedious synthetic routes and harsh reaction conditions and affords the product in 41% yield.

A practical approach for the synthesis of cyclic phenyl hexayne from Me₃Si-/Ph₂P(O)-protected ethyne is demonstrated through a one-pot deprotection/transformation of magnesium acetylide into a copper acetylide/Sonogashira coupling procedure, followed by dephosphination, Hay coupling, desilylation, and Eglinton coupling.

Introduction

Inherently nucleophilic alkynes, important building blocks for preparation of biological active compounds and organic functional compounds, are widely used in organic synthesis.^1–11 Phenyl polyynes, ¹² especially highly π-conjugated cyclic phenyl polyynes having rigid structures and highly expanded π-systems, can be widely used in organic materials such as organic field-effect transistors (OFETs), ¹³ organic light-emitting diodes (OLEDs), ¹⁴ dye-sensitized solar cells (DSSCs), ¹⁵ semiconductors, ¹⁶ and liquid crystals. ¹⁷ Transition-metal-catalyzed cross-coupling reactions^18–23 are efficient approaches for synthesis of polyynes. Haley has synthesized the cyclic phenyl hexayne 1 successfully by repeating Sonogashira coupling/desilylation, iodination, and desilylation/Eglinton coupling. However, this synthetic route required transformation of aryl diethyltriazene (Ar-N₃Et₂) compounds into Ar-I species by heating in a pressure bottle and in situ desilylation of tetramethylsilane (TMS)-protected butadiynes and Sonogashira coupling of the terminal butadiyne moiety with aryl iodides under strictly controlled reaction conditions (Scheme 1).^24,25 Since we developed a polar diphenylphosphoryl group, Ph₂P(O), for terminal ethynes, ²⁶ herein we have employed this chemistry for the synthesis of cyclic phenyl hexayne with a high total yield from Me₃Si-/Ph₂P(O)-protected ethynes by a simple and short synthetic route under mild reaction conditions.

Scheme 1.

Haley’s procedure for the synthesis of cyclic pentayne 1.

Results and discussions

We initiated our studies with the synthesis of expanded Me₃Si-/Ph₂P(O)-protected ethyne 6 from Me₃Si-/Ph₂P(O)-protected diyne 2 ²⁷ through a one-pot procedure. Treatment of Me₃Si-/Ph₂P(O)-protected ethyne 2 with methylmagnesium bromide afforded magnesium acetylide 3. Addition of copper iodide to the above reaction mixture transformed magnesium acetylide 3 into copper acetylide 4. Sonogashira coupling of 4 and iodide 5 ²⁷ gave the desired expanded Me₃Si-/Ph₂P(O)-protected ethyne 6 in 88% yield. This synthetic process was a one-pot procedure without isolation of intermediates 3 and 4 (Scheme 2).

Scheme 2.

Synthesis of expanded Me₃Si-/Ph₂P(O)-protected ethyne 6.

Without transformation of the magnesium acetylide 3 into copper acetylide 4, the direct coupling reaction between 3 and 5 afforded 6 as a mixture, which could not be isolated from by-products (Scheme 3). The reason for this is because the magnesium acetylide 3 is attacked by the Ph₂(O)P group in 5, yielding a series of by-products.

Scheme 3.

Synthesis of expanded Me₃Si-/Ph₂P(O)-protected ethyne 6 without transformation of 3 into 4.

With triyne 6 in hand, we synthesized cyclic phenyl hexayne 1 through dephosphination, Hay coupling, desilylation, and Eglinton coupling. Subjecting 6 to MeMgBr-catalyzed dephosphination gave magnesium acetylide 7 (Scheme 4). Without isolation of 7, direct addition of CuCl, piperidine, and toluene into the reaction mixture produced the desired Hay coupling product 8. Treatment of 8 with tetrabutylammonium fluoride (TBAF) afforded terminal diyne 9. When 9 was subjected to Cu(OAc)₂-catalyzed Eglinton coupling, the expected cyclization occurred to yield cyclic phenyl hexayne 1 in 41% yield (total yield over 4 steps). In this synthetic route, filtration of crude products 8 and 9 over a thin pad of silica gel was appropriate to give the intermediates 8 and 9 in sufficient purity for the subsequent reactions.

Scheme 4.

Synthesis of cyclic phenyl hexayne 1 from expanded Me₃Si-/Ph₂P(O)-protected ethyne 6.

Conclusion

In conclusion, we have developed an efficient procedure for the synthesis of cyclic phenyl hexayne from Me₃Si-/Ph₂P(O)-protected ethynes through a one-pot deprotection/transformation of magnesium acetylide into copper acetylide/Sonogashira coupling procedure followed by dephosphination, Hay coupling, desilylation, and Eglinton coupling. Our procedure demonstrates some advantages over the previous route, such as a short sequence, mild reaction conditions, and a high total yield.

Experiment

Dry solvents, reagents, and catalysts were purchased as analytical grade and used without further purification. Starting materials 2 and 5 were synthesized according to literature procedures. ¹⁶ Analytical thin-layer chromatography (TLC) was performed with brand silica gel 60 F254 plates. Column chromatography was carried out using brand silica gel 60 (200–300 mesh). Melting points were measured on a SGW X-4 (INESA) melting point apparatus and were uncorrected. All NMR spectra were recorded on a Bruker AV-II 500 MHz NMR spectrometer operating at 500 MHz for ¹H and at 125 MHz for ¹³C. TMS was used as an internal reference for ¹H and ¹³C chemical shifts, and CDCl₃ was used as the solvent. High-resolution mass spectra (MS) were obtained using electron ionization on a Bruker MicrOTOF II mass spectrometer.

Synthesis of 6

To a tetrahydrofuran (THF) solution (10.0 mL) of 2 (398.5 mg, 1.0 mmol), MeMgBr (3.0 M in diethyl ether, 333.3 μL, 1.0 mmol) was added. After the mixture had been stirred for 30 min under nitrogen at rt, CuI (228.5 mg, 1.2 mmol) was added at 0 °C. After the mixture was stirred under nitrogen at rt for 2.5 h, iodide 5 (342.6 mg, 0.8 mmol), Pd(PPh₃)₄ (57.8 mg, 0.05 mmol), toluene (16.0 mL), and diisopropylamine (0.5 mL) were added sequentially. The mixture was stirred under nitrogen at 50 °C for 20 h. After cooling, the mixture was extracted with CH₂Cl₂ and washed with NH₄Claq. The organic layer was washed with brine and dried over MgSO₄. After filtration, the solvents were evaporated. The crude residue was subjected to column chromatography on silica gel (hexane:EtOAc, 1:1) to give 6 in pure form. Triyne 6 ²⁷ is a known compound and its spectroscopic data have previously been reported.

6: White powder; m.p. 110–111 °C (lit. ²⁷ 112–113 °C); ¹H NMR (500 MHz, CDCl₃): δ = 0.22 (s, 9H), 7.11–7.15 (m, 1H), 7.16–7.18 (m, 1H), 7.25–7.28 (m, 4H), 7.35–7.37 (m, 5H), 7.43–7.48 (m, 3H), 7.51 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.91–7.95 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ = −0.11 (d, J = 4.1 Hz), 86.33 (d, J = 168.4 Hz), 90.90, 93.09, 99.07, 103.17, 103.52 (d, J = 29.4 Hz), 122.26 (d, J = 3.6 Hz), 125.26, 125.76, 126.89 (d, J = 1.5 Hz), 128.12–128.27 (m), 128.46–128.62 (m), 130.21, 130.91 (d, J = 11.4 Hz), 132.02 (d, J = 2.0 Hz), 132.27, 132.99 (d, J = 122.0 Hz), 133.02; HRMS (FAB) calcd for C₃₃H₂₈OPSi [M+H]: 499.1569, found: 499.1573.

Synthesis of cyclic phenyl hexayne 1

To a THF solution (5 mL) of 6 (498.2 mg, 1 mmol), MeMgBr (3.0 M in diethyl ether, 334 μL, 1 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 30 min. Next, CuCl (9.8 mg, 0.1 mmol), piperidine (49.6 μL, 0.5 mmol), and toluene (10.0 mL) were added to the mixture, which was stirred under air at 75 °C for 15 h. After cooling, the mixture was extracted with CH₂Cl₂ and washed with NH₄Claq. The combined organic layer was washed with brine and dried over MgSO₄. After filtration over a thin pad of silica gel, the solvents were evaporated to afford the crude product 8 in a sufficiently pure form for further reaction. To the crude product 8, water (0.5 mL) and THF (50.0 mL) were added, followed by TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol) at 0 °C, and the mixture was stirred under air at rt for 6 h. The mixture was extracted with CH₂Cl₂ and washed with NH₄Claq. The combined organic layer was washed with brine and dried over MgSO₄. After filtration over a thin pad of silica gel, the solvents were evaporated to afford the crude product 9 in a sufficiently pure form for further reaction. The crude product 9 was diluted with pyridine (100.0 mL) and methanol (100.0 mL). This solution was added to a 0.05-M solution consisting of Cu(OAc)₂(H₂O) (399.3 mg, 2 mmol) in a 6:6:1 mixture of pyridine, methanol, and Et₂O at 48 °C via a syringe over 16 h. And the mixture was stirred under air for 15 h. After cooling, the mixture was concentrated and the residue was diluted with CH₂Cl₂ and stirred vigorously with 10% HCl solution for 30 min. The organic layer was subsequently washed with dilute sodium bicarbonate solution, water, and then brine, followed by drying over MgSO₄. After filtration, the solvents were evaporated. The crude residue was subjected to column chromatography on silica gel (hexane:CH₂Cl₂, 8:1) to afford 1 in a pure form. Hexayne 1 ²⁴ is a known compound and its spectroscopic data have previously been reported.

1: Pale-yellow powder; m.p. 82–85 °C; ¹H NMR (500 MHz, CDCl₃): δ = 7.27–7.30 (m, 4H), 7.31–7.36 (m, 4H), 7.54 (s, 4H), 7.55 (s, 4H); ¹³C NMR (125 MHz, CDCl₃): δ = 78.09, 80.99, 91.59, 125.05, 126.44, 128.22, 128.66, 131.66, 133.21.

Supplemental Material

supplementary_material – Supplemental material for Synthesis of cyclic phenyl hexayne from Me₃Si-/Ph₂P(O)-protected ethynes

Supplemental material, supplementary_material for Synthesis of cyclic phenyl hexayne from Me₃Si-/Ph₂P(O)-protected ethynes by Li Wu, Li-fen Peng, Zhi-fang Hu, Hong Wang, Zi-long Tang, Yin-chun Jiao and Xin-hua Xu in Journal of Chemical Research