L. Pisco et al. / European Journal of Medicinal Chemistry 41 (2006) 401–407
405
diluted sodium hydrogen sulfate solution, then with water,
dried with Na2SO4 and evaporated under reduced pressure.
The residue was purified by column chromatography on silica
gel 60 (63–200 mesh, Merck) with the appropriate eluent.
C13H16O2 (204,26): calcd. C 76.44, H 7.89; found: C 76.45,
H 7.82.
6.1.2.3. 2-Hydroxy-3-(1,1-dimethylallyl)acetophenone
(4).
Compound 2 (1 mmol) was reacted at 180 °C for 5 h according
to Methods B. The resulting residues were purified by chroma-
tographic column on silica gel (toluene/ethylacetate 9.5:0.5).
C13H16O2 (204,26); Yield 57 mg (28%); colorless liquid. —
1H-NMR (300 MHz, CDCl3): δ = 13.10 (s, 1H, OH), 7.64
6.1.2. Methods B: general Claisen rearrangement procedure
The allylphenylether (1 mmol) was added to N,N-diethyla-
niline (10 ml) and the resulting mixture was stirred at 180 °C
or at 216 °C for 5 or 8 hours, respectively. Then, it was ex-
tracted with chloroform. The combined organic extracts were
washed with a hydrochloric acid-solution (15%) and finally
with water, dried with anhydrous Na2SO4 and evaporated un-
der reduced pressure. The residue was dissolved in methanol
(20 ml). A small amount of Amberlit IR-120 was added to the
solution. The resulting mixture was then stirred at room tem-
perature for 20 min and evaporated under reduced pressure.
Purification was carried out by column chromatography on si-
lica gel 60 (63–200 mesh; Merck).
3
4
(dd, 1H, J5′,6′ ≈ 8.0 Hz, J4′,6′ ≈ 1.5 Hz, H-6′), 7.49 (dd, 1H,
3J4′,5′ ≈ 8.0 Hz, H-4′), 6.83 (t, 1H, H-5′), 6.25 (dd, 1H, Jcis
≈
10.8 Hz, Jtrans ≈ 17.5 Hz, H-2′’), 5.10–4.95 (m, 2H, H-3′’),
2.63 (s, 3H, H-2), 1.50 (s, 6H, (CH3)2). — 13C-NMR
(75.5 MHz, CDCl3): δ = 205.1 (C=O), 161.7 (C-2′), 147.2
(C-2′’), 136.8 (C-3′), 134.1 (C-4′), 129.1 (C-6′), 119.6 (C-1′),
118.0 (C-5′), 110.5 (C-3′’), 40.6 (C-1′’), 27.0 (C-2), 26.8
((CH3)2). — MS (70 eV): m/z = 204 (M+), 189 (M+ –15
(CH3)), 161 (M+ –43 (CH3CO), 43 (CH3CO). — IR (film):
ν = 3435 (OH), 3030 (=CH aromat.), 2970, 2915 (CH3), 2855
(CH2), 1644 (C=O), 1587 (C=C) cm–1. C13H16O2 (204,26):
calcd. C 76.44, H 7.89; found: C 76.41, H 7.85.
6.1.2.1. 2-(3-Methylbut-2-enyloxy)acetophenone (2). A mixture
of o-hydroxy-acetophenone (1), (272 mg, 2 mmol), anhydrous
potassium carbonate (828 mg, 6 mmol) and dry DMF (10 ml)
was reacted with prenyl bromide (596 mg, 4 mmol) as de-
scribed under Methods A. The resulting residue was purified
by chromatographic column on silica gel (toluene/ethylacetate
9:1). Yield 347 mg (85%); colorless oil. — 1H-NMR
6.1.2.4. 5-(3-Methylbut-2-enyl)-2-(3-methylbut-2-enyloxy)acet-
ophenone (5). Compound 3 was reacted according to Methods
A. The resulting residue was purified by column chromatogra-
phy on silica gel (toluene/ethylacetate 9:1). C18H24O2 (272.37);
1
3
4
Yield 435 mg (80%); colorless liquid. — H-NMR (300 MHz,
(250 MHz, CDCl3): δ = 7.72 (dd, 1H, J5′,6′ ≈ 7.8 Hz, J4′,6′
≈
4
3
3
CDCl3): δ = 7.52 (d, 1H, J4′,6′ ≈ 2.5 Hz, H-6′), 7.23 (dd, 1H,
2.0 Hz, H-6′), 7.42 (ddd, 1H, J3′,4′ ≈ 8.5 Hz , J4′,5′ ≈ 7.5 Hz,
3
3J3′,4′ ≈ 8.5 Hz, H-4′), 6.86 (d, 1H, J3′,4′ ≈ 8.5 Hz, H-3′), 5.47
4J4′,6′ ≈ 2.0 Hz, H-4′), 6.96 (“dt”, 1H, J3′,5′ ≈ 1.0 Hz, H-5′),
4
3
3
(m, 1H, H-2′’), 5.26 (m, 1H, H-2′’’), 4.57 (d, 2H, J1′’,2′’
≈
6.95 (br d, 1H, J3′,4′ ≈ 8.5 Hz, H-3′), 5.49 (m, 1H, H-2′’), 4.6
(d, 2H, J1′’,2′’ ≈ 6.5 Hz, H-1′’), 2.61 (s, 3H, H-2), 1.79 (br m,
3
3
6.5 Hz, H-1′’), 3.27 (d, 2H, J1′’’,2′’’ ≈ 7.0 Hz,’H-1′’’), 2.6 (s,
3H, H-2), 1.77 (br m, 3H, CH3-prenyl), 1.72 (br s, 3H, CH3-
prenyl), 1.71 (br m, 3H, CH3-prenyl), 1.69 (br s, 3H, CH3-pre-
nyl). — 13C-NMR (62.9 MHz, CDCl3): δ = 200.2 (C=O),
156.6 (C-2′), 138.0 (C-3′’), 133.8 (C-5′), 133.2 (C-4′), 132.6
(C-3′’’), 129.9 (C-6′), 128.5 (C-1′), 123.0 (C-2′’’), 119.4 (C-
2′’), 112.9 (C-3′), 65.5 (C-1′’), 33.2 (C-1′’’), 32.0 (C-2), 25.7
(CH3-prenyl), 25.7 (CH3-prenyl), 18.2 (CH3-prenyl), 17.8
(CH3-prenyl). — IR (film): ν = 3070, 3026 (=CH), 2970
(CH3), 2879 (CH2), 1678 (C=O), 1236 (C–O) cm–1. —
C18H24O2 (272.37): calcd. C 79.37, H 8.88; found: C 79.32,
H 8.85.
3H, CH3-prenyl), 1.74 (br s, 3H, CH3-prenyl). – 13C-NMR
(62.9 MHz, CDCl3): δ = 200.0 (C=O), 158.3 (C-2′), 138.2
(C-3′’), 133.5 (C-4′), 130.3 (C-6′), 128.5 (C-1′), 120.4 (C-5′),
119.1 (C-2′’), 112.7 (C-3′), 65.3 (C-1′’), 32.0 (C-2), 25.7 (CH3
-prenyl), 18.2 (CH3-prenyl). — IR (film): ν = 3072, 3028
(=CH), 2976 (CH3), 2879 (CH2), 1674 (C=O), 1236 (C–O)
cm–1. — C13H16O2 (204,26): calcd. C 76.44, H 7.89; found
C 76.43, H 7.81.
6.1.2.2. 2-Hydroxy-5-(3-methylbut-2-enyl)acetophenone
(3).
Compound 2 was reacted according to Methods B at 216 °C
for 8 h. The resulting residue was purified by column chroma-
tography on silica gel (toluene/ethylacetate 9.5:0.5). Yield
143 mg (70%); colorless liquid. — 1H-NMR (300 MHz,
6.1.2.5. 6-(3-Methylbut-2-enyl)chromone-3-carbaldehyde (6).
To a solution of compound 3 (817 mg, 4 mmol) in dry DMF
(2 ml) was added phosphoryl chloride (1.23 g, 8 mmol) drop-
wise at 0 °C. The resulting mixture was heated at 45 °C for 1 h,
poured into cold water (15 ml) and extracted with chloroform.
The combined organic layers were dried with anhydrous so-
dium sulfate and evaporated under reduced pressure. The resi-
due was purified by column chromatography on silica gel (n-
hexane/ethylacetate 1:0,1). C15H14O3 (242.26); Yield 106 mg
(11%); white solid. — 1H-NMR (300 MHz, CDCl3): δ = 10.36
4
CDCl3): δ = 12.12 (s, 1H, OH), 7.49 (d, 1H, J4′,6′ ≈ 2.2 Hz,
3
4
H-6′), 7.29 (dd, 1H, J3′,4′ ≈ 8.5 Hz, J4′,6′ ≈ 2.2 Hz, H-4′), 6.9
(d, 1H, 3J3′,4′ ≈ 8.5 Hz, H-3′), 5.28 (m, 1H, H-2′’), 3.29 (d, 2H,
3J1′’,2′’ ≈ 7.5 Hz, H-1′’), 2.61 (s, 3H, H-2), 1.76 (br s, 3H, CH3-
prenyl), 1.72 (br s, 3H, CH3-prenyl). — 13C-NMR (62.9 MHz,
CDCl3): δ = 204.4 (C=O), 160.5 (C-2′), 136.8 (C-4′), 133.1 (C-
3′’), 132.1 (C-5′), 129.7 (C-6′), 122.8 (C-2′’), 119.4 (C-1′),
118.3 (C-3′), 33.4 (C-1′’), 26.6 (C-2), 25.7 (CH3-prenyl), 17.8
(CH3-prenyl). — MS (70 eV): m/z = 204, 189 (M+ –15 (CH3)),
161 (M+ –43 (CH3CO)), 69 (C5H9 prenyl), 43 (CH3CO). — IR
(film): ν = 3437.6 (OH), 3029 (=CH aromat.), 2971, 2916
(CH3), 2857 (CH2), 1642.8 (C=O), 1589 (C=C) cm–1. —
4
(s, 1H, CHO), 8.5 (s, 1H, H-2), 8.05 (d, 1H, J5,7 ≈ 2.2 Hz, H-
3
3
5), 7.54 (dd, 1H, J7,8 ≈ 8.5 Hz, H-7), 7.42 (d, 1H, J7,8
≈
3
8.5 Hz, H-8), 5.3 (m, 1H, H-2′), 3.44 (d, 2H, J1′,2′ ≈ 7.5 Hz,
H-1′), 1.75 (br m, 3H, CH3-prenyl), 1.71 (br s, 3H, CH3-pre-