Mild Pd/Cu-Catalyzed Sila-Sonogashira Coupling of (Hetero)aryl Bromides with (Hetero)arylethynylsilanes under PTC Conditions

Abstract

The palladium/copper cocatalyzed sila-Sonogashira reaction of (hetero)arylethynysilanes with (hetero)aryl bromides in toluene and water at 40 ˚C under PTC conditions gave the required di(hetero)arylethynes in moderate to high yields. Activated, deactivated and ortho-substituted (hetero)aryl bromides are well tolerated. This protocol also allowed the preparation of symmetrical diarylethynes by double arylation of 1,2-bis(trimethylsilyl)ethyne.

Sonogashira reaction - palladium - alkynylsilanes - di­arylethynes - copper - phase-transfer catalysis

References and Notes

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<A NAME="RD80911ST-22">22</A>

General Procedure for the Synthesis of Di(hetero)arylethynes 3
To a mixture of alkynyltrimethylsilane 1 (1 mmol), (hetero)aryl bromide 2 (1.1 mmol), PdCl₂(PhCN)₂ (19.8 mg, 0.05 mmol), t-Bu₃PHBF₄ (29.0 mg, 0.1 mmol), CuI (19.0 mg, 0.1 mmol), and Bn(n-Bu)₃NCl (62.4 mg, 0.2 mmol) in toluene (8 mL) was added a 2.5 M aq solution of NaOH (10 mmol, 4 mL), and the resulting biphasic mixture was stirred under argon at 40 ˚C for the period of time reported in Table  [²] . The degree of completion of the reaction and the composition of the reaction mixture were established by GC and GC-MS analyses of a sample of the crude reaction mixture after it had been treated with a sat. aq NH₄Cl solution and extracted with EtOAc. After being cooled to r.t., the reaction mixture was diluted with EtOAc (15 mL) and poured into a sat. aq NH₄Cl solution (15 mL), and the resulting mixture was stirred in the open air for 0.5 h and then extracted with EtOAc (4 × 10 mL). The organic extracts were washed with H₂O (2 × 5 mL), dried and concentrated under reduced pressure, and the residue was purified by flash cromatography on silica gel. This procedure was employed to prepare di(hetero)arylethynes 3a-e,g-m (Table  [²] , entries 1-5 and 7-10,). The same procedure, but employing BTSE (0.23 mL, 0.17 g, 1.0 mmol) and aryl bromide 2 (2.2 mmol), was also applied to the synthesis of symmetrically substituted diarylethynes 4a-c (Scheme  [³] ).

<A NAME="RD80911ST-23">23</A>

Representative Data for New Compounds
4-(Thiophen-2-ylethynyl)benzaldehyde (3g)
Mp 110-112 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.03 (dd, J = 3.7, 5.0 Hz, 1 H), 7.34 (m, 2 H), 7.63 (d, J = 9.0 Hz, 2 H), 7.84 (d, J = 9.0 Hz, 2 H), 9.99 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 86.87, 92.37, 122.43, 127.40, 128.43, 129.20, 129.62 (2 C), 131.79 (2 C), 132.93, 135.40, 191.39. MS: m/z (%) = 212 (100) [M⁺], 211 (60), 183 (13), 139 (35), 91 (6). Anal. Calcd for C₁₃H₈OS (212.27): C, 73.56; H, 3.80. Found: C, 73.84; H, 3.78.
3-[(3,4-Dimethoxyphenyl)ethynyl]pyridine (3l)
Mp 53-55 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 3.89 (m, 6 H), 6.83 (d, J = 9 Hz, 1 H), 7.05 (s, 1 H), 7.16 (d, J = 6 Hz, 1 H), 7.25 (m, 1 H), 7.77 (d, J = 9 Hz, 1 H), 8.55 (s, 1 H), 8.79 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 55.67, 55.70, 84.48, 92.75, 110.83, 113.99, 114.40, 120.57, 122.91, 124.94, 137.98, 148.06, 148.46, 149.67, 151.85. MS: m/z (%) = 239 (100) [M⁺], 224 (18), 196 (16), 167 (27), 1543 (12), 127 (12). Anal. Calcd for C₁₅H₁₃NO₂ (239.27): C, 75.30; H, 5.48. Found: C, 75.61; H, 5.52.

<A NAME="RD80911ST-24">24</A> Recently, a classical Sonogashira cross-coupling protocol for the synthesis of compounds 3 was published: Moulton BE. Whitwood AC. Duhme-Klair AK. Lynam JM. Fairlamb IJS. J. Org. Chem.  2011,  76:  5320