A Stable Reagent for Synthesis of Conjugated Enynes from Enals

Abstract

Several conjugated enynes, which were not accessible if using the Ohira-Bestmann reagent, were synthesized from the corresponding enals using a newly developed reagent that has a longer shelf lifetime and can be activated under mild conditions.

Key words

alkynes - Wittig reactions - elimination - carbenes - phosphates

References and Notes

• 1a Seyferth D. Marmor RS. Tetrahedron Lett.  1970,  2493 
• 1b Seyferth D. Marmor RS. Hilbert P. J. Org. Chem.  1971,  36:  1379 
• 1c Brown DG. Velthuisen EJ. Commerford JR. Brisbois RG. Hoye TR. J. Org. Chem.  1996,  61:  2540 
• 1d Colvin EW. Hamill BJ.
  J. Chem. Soc., Chem. Commun.  1973,  151 
• 1e Gilbert JC. Weerasooriya U. J. Org. Chem.  1979,  44:  4997 
• 1f Gilbert JC. Weerasooriya U. J. Org. Chem.  1982,  74:  1837 
• 1g A referee informed us that Maehr et al. recently reported that 1 is more stable than previously believed and could be stored in refrigerators for years, see: Maehr H. Uskokovic MR. Schaffner CP. Synth. Commun.  2009,  39:  299 
• 2a Ohira S. Synth. Commun.  1989,  19:  561 
• 2b Roth GJ. Liepold B. Müller S. Bestmann HJ. Synthesis  2004,  59 
• 2c Müller S. Liepold B. Roth GJ. Bestmann HJ. Synlett  1996,  521 
• 3 Teulade M.-P. Savignac P. Aboujaoude EE. Collignon N. J. Organomet. Chem.  1986,  312:  283 
• 4 Ditrich K. Hoffmann RW. Tetrahedron Lett.  1985,  26:  6325 
• 6 For the reaction of diakyl methylphosphate with γ-butyrolactone, see: Ditrich K. Hoffmann RW. Tetrahedron Lett.  1985,  26:  6325 

5

Synthesis of Compound 3
n-BuLi (2.5 M in hexanes, 15.76 mL, 39.4 mmol) was added to a solution of 4 (6.0 g, 39.4 mmol) in dry THF (40 mL) stirred at -78 ˚C under argon. The mixture was stirred at the same temperature for 1 h before a solution of γ-butyro-lactone (2.15 mL, 28 mmol) in dry THF (5 mL) was introduced. The originally slightly cloudy mixture now became clear. The bath temperature was allowed to rise slowly to ambient temperature. The stirring was then continued for another 2 h. After that, the bath was re-cooled to -78 ˚C before a solution of LDA (28 mmol, freshly prepared from 4.0 mL of i-Pr₂NH and 11.2 mL of 2.5 M n-BuLi) in dry THF (20 mL) was introduced. The mixture was stirred for 30 min. TESCl (9.4 mL, 56 mmol) was then added. The mixture was stirred at ambient temperature overnight. Aq sat. NH₄Cl was added, followed by EtOAc. The phases were separated. The organic layer was washed with H₂O and brine before being dried over anhyd Na₂SO₄. Removal of the solvent by rotary evaporation and column chromatography (PE-EtOAc = 1:1 to 1:2) on silica gel gave the intermediate acyl phosphate 4b as a colorless oil (8.57 g, 87% from 4).
A portion of this oil (4b, 7.596 g, 21.5 mmol) was dissolved in THF (30 mL). With cooling (ice-water bath) and stirring, powdered K₂CO₃ (3.3 g, 23.9 mmol) was added, followed by TsN₃ (4.7 g, 23.9 mmol). The mixture was stirred at the bath temperature for 2 h and then at ambient temperature overnight before being diluted with Et₂O, washed with aq sat. NH₄Cl, and dried over anhyd Na₂SO₄. Removal of the solvent by rotary evaporation and column chromatography (PE-EtOAc = 3:1) on silica gel gave 5 as a colorless oil
(5.53 g, 68% from the intermediate acyl phosphate).
^¹H NMR (300 MHz, CDCl₃): δ = 4.25-4.08 (m, 4 H), 3.65 (t, J = 6.0 Hz, 2 H), 2.66 (t, J = 7.3 Hz, 2 H), 1.86 (quin, J = 6.6 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 6 H), 0.96 (t, J = 7.9 Hz, 9 H), 0.59 (q, J = 7.9 Hz, 6 H). FT-IR (film): 3412, 2955, 2123, 1659, 1253, 1019, 977, 742, 589 cm^-¹. ESI-MS: m/z = 401.1 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₅H₃₁N₂O₅PSiNa: 401.1632 [M + Na]⁺; found: 401.1634.
AcOH (11 mL) was added slowly to a solution of 5 (2.5 g, 6.76 mmol) in THF-H₂O (20 mL, 1:1 v/v) stirred in an ice-water bath. After completion of the addition, the mixture was stirred at the same temperature for another 10 min. Na₂CO₃ was carefully added to neutralize the acid. The mixture was extracted with EtOAc. The combined organic layers were concentrated on a rotary evaporator. The residue was chromatographed (PE-EtOAc = 1:2) on silica gel to give 3 as yellowish oil (1.25 g, 4.73 mmol, 70%).
^¹H NMR (300 MHz, CDCl₃): δ = 4.30-4.10 (m, 4 H), 3.66 (t, J = 6.1 Hz, 2 H), 2.72 (t, J = 6.9 Hz, 2 H), 2.10-1.90 (br s, 1 H), 1.92 (quin, J = 6.5 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 193.2 (d, J _C-P = 14 Hz), 63.5 (d, J _C-P = 6 Hz), 61.3, 35.9, 27.1, 15.9 (d, J _C-P = 7 Hz). FT-IR (film): 3443, 2986, 2118, 1656, 1369, 1251, 1032, 977, 593 cm^-¹. ESI-MS: m/z = 287.0 [M + Na]⁺. ESI-HRMS: m/z calcd for C₉H₁₇N₂O₅PNa: 287.0767 [M + Na]⁺; found: 287.0769.

7

In the absence of the crown ether, the reaction was very slow; most of the starting enal (except 6a) remained unchanged after 4-5 h at -78 ˚C along with some uncharacterized intermediates and small amounts of the desired enyne.

8

General Procedure for the Conversion of 6 into 7
NaHMDS (2.0 M in THF, 55 µL, 0.11 mmol) was added to a solution of 3 (29 mg, 0.11 mmol) in dry THF (1.0 mL) stirred at -78 ˚C under argon. The mixture was stirred at the same temperature for 30 min, when a solution of enal 6 (0.073 mmol) in dry THF (0.5 mL) was added slowly (the mixture darkened soon). 15-Crown-5 ether (22 µL, 0.11 mmol) was then added in one portion. The mixture was stirred at the same temperature for 1 h. Aq sat. NH₄Cl was added, followed by Et₂O. The phases were separated. The organic layer was dried over anhyd Na₂SO₄. Removal of the solvent by rotary evaporation and column chromatography on silica gel gave the corresponding 7.