Synthesis of 3-Alkylidenebicyclo[3.2.1]octan-8-one Skeleton from the Baylis-Hillman Acetates

Abstract

Synthesis of 3-alkylidenebicyclo[3.2.1]octan-8-one skeleton 4 from Baylis-Hillman acetates 1 was carried out under kinetically controlled conditions: K₂CO₃ in ethanol at room tem­perature.

Key words

3-alkylidenebicyclo[3.2.1]octan-8-one - Baylis-Hillman acetate - kinetically controlled conditions

References

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8

Synthesis of 3a and 4a (typical procedure): To a stirred mixture of Baylis-Hillman acetate 1a (109 mg, 0.5 mmol) and ethyl 2-oxocyclopentanecarboxylate (78 mg, 0.5 mmol) in ethanol (3 mL) was added K₂CO₃ (76 mg, 0.55 mmol) and stirred at room temperature for 22 h. After the usual workup process and column chromatographic purification (hexane/diethyl ether = 4:1) desired products 3a (24 mg, 15%) and 4a (E, 91 mg, 58%) were obtained as clear oils. During separation Z-form of 4a was isolated also (20 mg, 13%). Selected data of prepared compounds are as follows. 3a: ¹H NMR (CDCl₃) δ 1.13 (t, J = 7.2 Hz, 3 H), 1.65-1.82 (m, 3 H), 2.14-2.38 (m, 3 H), 2.45 (s, 3 H), 2.98 (d, J = 14.2 Hz, 1 H), 3.38 (d, J = 14.2 Hz, 1 H), 3.88-4.04 (m, 2 H), 7.30-7.42 (m, 5 H), 7.58 (s, 1 H). 4a (E-form): ¹H NMR (CDCl₃) δ 1.26 (t, J = 7.1 Hz, 3 H), 1.46 (s, 3 H), 1.59-1.67 (m, 1 H), 1.85-1.95 (m, 2 H), 2.34 (s, 1 H, OH), 2.35-2.41 (m, 1 H), 2.43-2.45 (m, 1 H), 2.75 (dt, J = 15.2 Hz and 2.2 Hz, 1 H), 3.08 (d, J = 15.2 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 7.09 (d, J = 2.2 Hz, 1 H), 7.21-7.38 (m, 5 H); ¹³C NMR (CDCl₃) δ 14.10, 18.09, 26.19, 27.81, 35.44, 57.53, 58.32, 61.37, 78.72, 126.96, 127.58, 128.28, 129.20, 136.58, 139.15, 170.67, 209.50; CIMS m/z (rel. intensity) 75 (100), 83 (70), 157 (54), 173 (57), 201 (45), 219 (60), 269 (51), 297 (42), 315 (M⁺ + 1, 75). 4a (Z-form): ¹H NMR (CDCl₃) δ 1.25 (t, J = 7.2 Hz, 3 H), 1.59 (s, 3 H), 1.50-2.00 (m, 3 H), 2.19 (br s, 1 H), 2.34-2.45 (m, 2 H), 3.05 (d, J = 14.4 Hz, 1 H), 3.23 (dt, J = 14.4 Hz and 2.1 Hz, 1 H), 4.18 (qd, J = 7.2 Hz and 1.3 Hz, 2 H), 6.82 (d, J = 1.9 Hz, 1 H), 7.21-7.40 (m, 5 H); ¹³C NMR (CDCl₃) δ 14.17, 19.51, 25.08, 26.15, 37.18, 56.96, 57.13, 61.35, 81.64, 127.30, 128.41, 128.96, 129.19, 136.45, 138.05, 170.73, 209.94.
Synthesis of 5a and 6a (typical procedure): To a stirred mixture of Baylis-Hillman acetate 1a (153 mg, 0.7 mmol) and ethyl 2-oxocyclopentanecarboxylate (110 mg, 0.7 mmol) in ethanol (3 mL) was added K₂CO₃ (110 mg, 0.8 mmol) and heated to reflux for 1 h. After the usual workup process and column chromatographic purification (hexane/ethyl acetate = 4:1) desired products 5a (90 mg, 41%) and 6a (48 mg, 23%) were obtained as clear oils. Selected data of prepared compounds are as follows. 5a: ¹H NMR (CDCl₃) δ 1.05 (t, J = 7.1 Hz, 3 H), 1.66-1.96 (m, 5 H), 2.35-2.42 (m, 1 H), 2.71 (dd, J = 15.8 Hz and 2.0 Hz, 1 H), 2.90 and 2.95 (2 d, J = 16.5 Hz, 1 H each, C=C-CH₂), 3.46 (dd, J = 15.8 Hz and 1.4 Hz, 1 H), 4.06 (q, J = 7.1 Hz, 2 H), 7.27-7.44 (m, 5 H), 7.59 (s, 1 H); ¹³C NMR (CDCl₃) δ 13.83, 21.09, 33.43, 35.49, 40.16, 50.01, 56.21, 61.23, 81.23, 128.49, 128.79, 129.87, 132.99, 135.03, 136.84, 175.50, 199.32; CIMS m/z (rel. intensity) 117 (19), 269 (15), 297 (100), 315 (M⁺+1, 2). 6a: ¹H NMR (CDCl₃) δ 1.02 (t, J = 7.1 Hz, 3 H), 1.68-2.82 (m, 6 H), 2.55 (dd, J = 14.4 Hz and 2.8 Hz, 1 H), 3.87 (d, J = 14.4 Hz, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 6.19 (t, J = 2.0 Hz, 1 H), 7.21-7.45 (m, 5 H), 7.65 (d, J = 2.8 Hz, 1H); ¹³C NMR (CDCl₃) δ 13.85, 22.58, 31.91, 37.08, 38.12, 54.74, 61.41, 124.16, 128.34, 128.41, 129.45, 131.95, 135.64, 136.03, 168.47, 173.05, 186.16; EIMS (70 eV) m/z (rel. intensity) 115 (79), 165 (77), 195 (41), 223 (96), 295 (100), 296 (M⁺, 84).

9

The reaction of the bicyclic compound 4a in ethanol in the presence of K₂CO₃ (1.1 equiv) at reflux temperature for 30 min gave the thermodynamic products 5a (36%) and 6a (20%).

11

The stereochemistry of 4a was confirmed by NOE experiments (Figure [1] ). The stereochemistry between the methyl group at C-2 position and the proton at C-1 position might be cis relationship.