Beilstein J. Org. Chem. 2011, 7, 1323–1326.
(Scheme 3). Acid 3 was converted to the acid chloride 2 by 15 minutes. Next, a saturated NaHCO3 solution (6 mL) and
treatment of oxalyl chloride [10]. In situ addition of indium(III) THF (3 mL) were added and stirred for 15 minutes, followed by
chloride promoted cyclization of 2 to 3-chloro-2-cyclo- addition of NaOH (10% aq, 6 mL) and 5 minutes of stirring.
hexenone (4) and was followed by quenching with alcohol The mixture was extracted with dichloromethane (3 × 10 mL)
nucleophiles, yielding 3-alkoxy-2-cyclohexenones 1.
and the combined organic layers were dried over CaCl2 and
concentrated in vacuo. Solvent exchange with CHCl3 (2 ×
5 mL) gave the product (0.216 g, 1.71 mmol, 72%) as an oil.
1H NMR (300 MHz, CDCl3) δ 5.36 (s, 1H, CH), 3.68 (s, 3H,
CH3), 2.40 (t, J = 6.3 Hz, 2H, CH2), 2.34 (t, J = 6.5 Hz, 2H,
CH2), 1.97 (tt, J = 6.3, 6.5 Hz, 2H, CH2); 13C NMR (300 MHz,
CDCl3) δ 195.1, 174.3, 97.6, 50.9, 31.9, 24.0, 16.4; IR (ATR,
neat) 2946, 1645, 1603, 1378, 1225, 1186, 1135, 1003, 826,
757 cm−1; EIMS (m/z): 127.
3-Isopropoxy-2-cyclohexenone (1d): 5-Hexynoic acid
(0.241 g, 2.15 mmol) and oxalyl chloride (0.361 g, 2.84 mmol)
were combined with anhydrous dichloromethane (1.5 mL) in a
nitrogen-purged 25 mL round-bottom flask and stirred for
2.5 hours. Indium(III) chloride (0.522 g, 2.36 mmol) was added
and the mixture was stirred for 3 hours. 2-propanol (1.352 g,
22.5 mmol) was then added and the mixture was stirred for
15 minutes at 90 °C. The reaction mixture was cooled to room
temperature and a saturated NaHCO3 solution (6 mL) and THF
(3 mL) were added and stirred for 15 minutes, followed by ad-
dition of NaOH (10% aq, 6 mL) and 15 more minutes of stir-
ring. The mixture was extracted with DCM (2 × 15 mL) and the
combined organic layers were dried over CaCl2 and concen-
trated in vacuo. Solvent exchange with CHCl3 (3 × 5 mL) gave
Scheme 3: Proposed pathway for the one-pot conversion of
5-hexynoic acid to 3-alkoxy-2-cyclohexenones.
Related examples by Forsyth [2] and Clausen [4] support our
proposed mechanism. They reported conjugate addition of
alcohol nucleophiles to 3-chloro-2-cyclohexenone substrates
under basic conditions followed by elimination of the chloride.
The key difference between their reported conditions and ours
is that our cyclizations are Lewis acid mediated.
Building on the work of Tedder [7] and Smit [8,9] we have im- the pure product (0.245 g, 1.59 mmol, 74%) as an oil. 1H NMR
proved the alkynoic acid cyclization approach in a manner that (300 MHz, CDCl3) δ 5.33 (s, 1H, CH), 4.41 (sept., J = 6.1 Hz,
allows ready access to 3-alkoxy-2-cyclohexenones in good 1H, CH), 2.35 (t, J = 6.5 Hz, 2H, CH2), 2.32 (t, J = 7.1 Hz, 2H,
yields. Further elaboration of this methodology is ongoing. CH2), 1.95 (tt, J = 6.5, 7.1 Hz, 2H, CH2), 1.27 (d, J = 6.1 Hz,
6H, 2 CH3); 13C NMR (CDCl3) δ 195.4, 172.4, 98.3, 66.2, 31.9,
Experimental
24.8, 16.6; IR (ATR, neat): 2980, 1645, 1594, 1379, 1219,
General methods: All experiments were carried out under an 1183, 1105, 940, 824, 752 cm−1; EIMS (m/z): 155.
atmosphere of dry nitrogen in oven-dried glassware. Solvents,
1H NMR data for compounds 1a, 1c, 1e, 1f,
starting materials and reagents were purchased (Sigma-Aldrich
and Fisher Scientific) and used without further purification. 1H 1h–j and 4
and 13C NMR spectra were obtained on a Varian Gemini 2000 3-Ethoxy-2-cyclohexenone (1a): 1H NMR (300 MHz, CDCl3)
(300 MHz) spectrometer with CDCl3 as solvent. Infrared δ 5.34 (s, 1H, CH), 3.89 (q, J = 7.1 Hz, 2H, CH2), 2.39 (t, J =
spectra were obtained on a Thermo Nicolet 380 FT-IR spec- 6.3 Hz, 2H, CH2), 2.34 (t, J = 6.5 Hz, 2H, CH2), 1.97 (tt, J =
trometer with Smart IR ATR (Si or ZnSe). Mass spectra were 6.3, 6.5 Hz, 2H, CH2), 1.35 (t, J = 7.1 Hz, 3H, CH3).
taken with a Varian 3800 GC/Saturn 2000 MS (ion trap).
3-Propoxy-2-cyclohexenone (1c): 1H NMR (300 MHz, CDCl3)
3-Methoxy-2-cyclohexenone (1b): 5-Hexynoic acid (3) (0.267 δ 5.33 (s, 1H, CH), 3.76 (t, J = 6.5 Hz, 2H, CH2), 2.39 (t, J =
g, 2.38 mmol) was combined with oxalyl chloride (0.396 g, 6.3 Hz, 2H, CH2), 2.32 (t, J = 6.5 Hz, 2H, CH2), 1.96 (tt, J =
3.05 mmol) in anhydrous dichloromethane (1.5 mL) in a 6.3, 6.5 Hz, 2H, CH2), 1.73 (tq, J = 6.5, 7.1 Hz, 2H, CH2), 0.96
nitrogen-purged 25 mL round-bottom flask and stirred for (t, J = 7.4 Hz, 2H, CH3).
2.5 hours. Indium(III) chloride (0.565 g, 2.55 mmol) was added
and the mixture was stirred for 3 hours. Methanol (0.401 g, 3-Butoxy-2-cyclohexenone (1e): 1H NMR (300 MHz, CDCl3)
12.5 mmol) was then added and the mixture was stirred for δ 5.33 (s, 1H, CH), 3.81 (t, J = 6.5 Hz, 2H, CH2), 2.38 (t, J =
1325