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Synlett 2006(18): 3173-3175  
DOI: 10.1055/s-2006-948169
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Convenient Synthesis of Propargylic Dithioacetals

Li-Fu Huang, Chin-Fa Lee, Jui-Chang Tseng, Tien-Yau Luh*
Department of Chemistry, National Taiwan University, Taipei, Taiwan 106
Fax: +886(2)23644971; e-Mail: tyluh@ntu.edu.tw;
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Publication History

Received 12 April 2006
Publication Date:
04 August 2006 (online)

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Abstract

Treatment of trimethylsilyl-substituted alkynyl ketones with 1,2-ethanedithiol in the presence of BF3·OEt2 in methanol afforded the corresponding dithioacetal. Removal of the silyl group under basic conditions followed by palladium-catalyzed coupling reactions with aryl iodides yielded the corresponding propargylic dithioacetals in excellent yield.

Key words

propargylic dithioacetals - alkynyl Grignard - cross-coupling reactions - desilylation

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Synthesis of 5; General Procedure: To a solution of 4 (50 mmol) in MeOH (100 mL) cooled to - 78 °C were added BF3·OEt2 (60 mmol) and 1,2-ethanedithiol (51 mmol). The mixture was gradually warmed to r.t. and stirred for 12 h. After quenching with a 10% aq solution of NaOH, the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with a 10% aq solution of NaOH, brine, dried (MgSO4), filtered, and concentrated in vacuo to give the crude propargylic dithioacetal which was dissolved in MeOH (100 mL). To this methanolic solution was added K2CO3 (200 mmol) and a 10% aq solution of NaOH (25 mL).14 The mixture was stirred at r.t. overnight and then quenched with dilute HCl. CH2Cl2 was added and the aqueous layer was extracted with CH2Cl2. The combined organic solution was washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (hexane-EtOAc, 20:1) to give 5. Synthesis of 6; General Procedure A solution of Pd2(dba)3 (2.5-5.0 mol%) in THF (15 mL), PPh3 (10-20 mol%), and aryl iodide (1.0 mmol) were heated at 65-70 °C under an Ar atmosphere; a solution of the Grignard reagent (1.0 mmol) in THF (15 mL) was added dropwise [prepared from the corresponding 5 (1 equiv) and MeMgI (2.0 M, Et2O; 1.1 equiv)]. The mixture was refluxed for 10-12 h. After cooling to r.t., the mixture was quenched with a sat. solution of NH4Cl. Et2O was added and the organic layer was washed with brine, dried (MgSO4), and filtered. The filtrate was evaporated in vacuo, and the residue was chromatographed on silica gel (hexane-EtOAc, 20-30:1) to give 6. 6b: 1H NMR (CDCl3, 300 MHz): δ = 2.36 (s, 3 H), 3.65-3.90 (m, 4 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.30-7.45 (m, 5 H), 8.02 (d, J = 8.0 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 21.5, 41.3, 62.4, 87.1, 90.3, 119.6, 127.7, 128.2, 128.3, 129.0, 131.5, 138.5, 138.8. 6c: Mp 107-109 °C. 1H NMR (CDCl3, 300 MHz): δ = 3.65-3.90 (m, 4 H), 3.93 (s, 3 H), 7.30-7.42 (m, 3 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.95-8.10 (m, 4 H). 13C NMR (CDCl3, 100 MHz): δ = 41.4, 52.2, 62.0, 86.0, 94.1, 127.4, 128.3, 128.5, 129.4, 129.6, 131.5, 138.3, 166.5. 6d: Mp 56-58 °C. 1H NMR (CDCl3, 400 MHz): δ = 3.65-3.90 (m, 4 H), 7.30-7.55 (m, 7 H), 7.90-8.10 (m, 2 H). 13C (CDCl3, 100 MHz): δ = 41.4, 62.1, 85.7, 92.3, 121.7, 122.7, 127.6, 128.3, 128.4, 131.5, 133.1, 138.5. 6e: Mp 66-68 °C. 1H NMR (CDCl3, 300 MHz): δ = 3.65-3.80 (m, 4 H), 3.82 (s, 3 H), 6.86 (d, J = 7.3 Hz, 2 H), 7.28-7.50 (m, 5 H), 8.02 (d, J = 7.3 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 41.3, 55.3, 62.4, 86.8, 89.6, 113.8, 114.8, 127.6, 128.2, 128.3, 133.1, 139.0, 159.7. 6f: 1H NMR (CDCl3, 400 MHz): δ = 1.03 (t, J = 7.3 Hz, 3 H), 1.70-1.90 (m, 2 H), 2.15-2.35 (m, 2 H), 3.38-3.70 (m, 4 H), 7.28-7.55 (m, 5 H). 13C NMR (CDCl3, 100 MHz): δ = 14.0, 22.0, 39.7, 46.0, 60.0, 84.1, 91.8, 122.8, 128.1, 131.5. 6g: Mp 68-70 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.03 (t, J = 7.3 Hz, 3 H), 1.70-1.86 (m, 2 H), 2.15-2.30 (m, 2 H), 3.44-3.70 (m, 4 H), 3.91 (s, 3 H), 7.47 (d, J = 6.7 Hz, 2 H), 7.96 (d, J = 6.7 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 14.0, 22.0, 39.8, 45.8, 52.2, 59.8, 83.3, 95.0, 127.6, 129.3, 129.4, 131.5, 166.5. 6h: 1H NMR (CDCl3, 400 MHz): δ = 1.03 (t, J = 7.3 Hz, 3 H), 1.60-1.82 (m, 2 H), 2.10-2.26 (m, 2 H), 3.35-3.66 (m, 4 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 14.0, 22.0, 39.8, 46.0, 59.9, 83.0, 93.1, 121.8, 122.4, 131.4, 133.1. 6i: 1H NMR (CDCl3, 300 MHz): δ = 1.02 (t, J = 7.3 Hz, 3 H), 1.68-1.85 (m, 2 H), 2.15-2.25 (m, 2 H), 3.48-3.65 (m, 4 H), 3.80 (s, 3 H), 6.81 (d, J = 7.3 Hz, 2 H), 7.34 (d, J = 7.3 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 14.0, 22.0, 39.7, 46.3, 55.2, 60.3, 84.0, 90.4, 113.7, 114.9, 133.0, 159.5. 6j: Mp 93-94 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.33 (s, 9 H), 3.45-3.65 (m, 4 H), 3.91 (s, 3 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.96 (d, J = 8.2 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 27.6, 40.2, 40.4, 52.2, 71.6, 83.9, 95.8, 128.0, 129.2, 129.3, 131.4, 166.6. 6k: Mp 52-54 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.31 (s, 9 H), 3.35-3.48 (m, 2 H), 3.50-3.62 (m, 2 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 27.6, 40.3, 40.4, 71.6, 83.5, 93.9, 122.1, 122.2, 131.4, 132.9. 6l: Mp 160-161 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.60-1.80 (m, 6 H), 1.99 (br s, 6 H), 2.08 (br s, 3 H), 3.26-3.40 (m, 2 H), 3.45-3.60 (m, 2 H), 3.91 (s, 3 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.96 (d, J = 8.3 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 28.7, 36.6, 39.1, 39.8, 41.1, 52.2, 72.1, 84.5, 95.2, 128.1, 129.2, 129.3, 131.5, 166.6. 6m: Mp 66-68 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.60-1.80 (m, 6 H), 1.90-2.04 (m, 6 H), 2.06 (br s, 3 H), 3.30-3.42 (m, 2 H), 3.45-3.60 (m, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 37.4, 39.8, 40.5, 41.9, 72.7, 73.9, 84.5, 93.6, 122.2, 122.4, 131.4, 133.0. 6n: Mp 97-98 °C. 1H NMR (CDCl3, 300 MHz): δ = 1.40-1.58 (m, 5 H), 1.65-2.20 (m, 6 H), 3.40-3.64 (m, 4 H), 3.91 (s, 3 H), 7.47 (d, J = 7.1 Hz, 2 H), 7.96 (d, J = 7.1 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 25.8, 26.2, 31.7, 39.3, 50.0, 52.2, 66.1, 84.3, 94.3, 127.8, 129.3, 131.5, 166.5. Sonogashira Reaction of 5a A solution of 5a (206 mg, 1 mmol) in DMF (20 mL), iodobenzene (0.11 mL, 1 mmol), PdCl2 (PPh3) 2 (35 mg, 5 mol%), Ph3P (26 mg, 10 mol%), CuI (19 mg, 10 mol%), and Et3N (0.42 mL, 3 mmol) was stirred under an Ar atmosphere at 90 °C for 12 h. After cooling to r.t., the mixture was filtered (silica gel-celite,1:1) and the solvent was removed in vacuo to give the residue which was chromatographed on silica gel (hexane-EtOAc, 3:1) to give 6a as a white solid (205 mg, 73%). 1-[(2-Phenyl-1,3-dithiolan-2-yl)ethynyl]cyclohexanol ( 7) n-BuLi (2.5 M, hexane; 0.84 mL, 2.2 mmol) was added dropwise to a solution of 5a (412 mg, 2 mmol) in THF (30 mL) at -78 °C, and the resulting mixture was stirred for 30 min. Cyclohexanone (0.20 mL, 2 mmol) was then added, the dry-ice bath was removed, and the mixture was stirred at r.t. for 2 h. The reaction was quenched with a sat. solution of NH4Cl, Et2O was added, and the organic layer was washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (hexane-EtOAc, 3:1) to give 7 as a white powder (527 mg, 87%); mp 72-74 °C. IR (KBr): 3403 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.15-1.34 (m, 2 H), 1.48-1.65 (m, 4 H), 1.68-1.80 (m, 4 H), 1.97 (br s, 1 H), 3.62-3.80 (m, 4 H), 7.28-7.40 (m, 3 H), 7.94 (d, J = 8.0 Hz, 2 H). 13C NMR (CDCl3, 100 MHz): δ = 23.9, 25.6, 40.4, 41.6, 62.1, 69.3, 86.8, 90.9, 127.7, 128.4, 128.5, 138..8

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The reaction can also be carried out without NaOH, however, a higher reaction temperature (40-45 °C) was required.