The Heck Coupling Reaction Using Aryl Vinyl Ketones: Synthesis of Flavonoids
FULL PAPER
H, 5Ј-H), 6.86 (d, J ϭ 8.6 Hz, 1 H, 5-H), 7.10 (s, 1 H, 2-H), 7.17
(dd, J ϭ 8.6, J ϭ 2.2 Hz, 1 H, 6-H), 7.35 (d, J ϭ 16.2 Hz, 1 H, α-
H), 7.61 (d, J ϭ 16.2 Hz, 1 H, β-H),7.72 (d, J ϭ 8.4 Hz, 1 H,
6Ј-H) ppm. 13C NMR (CDCl3): δ ϭ 56.0, 55.6 (3 ϫ OCH3,
1 ϫ OCH3, C-2Ј, C-4Ј, C-3, C-4), 98.7 (C-3Ј), 105.4 (C-5Ј), 110.5
(C-5*), 111.4 (C-2*), 122.4 (C-1Ј), 122.6 (C-6), 125.4 (C-α), 128.5
(C-1), 132.6 (C-6Ј), 142.3 (C-β), 149.3 (C-4**), 151.1 (C-3**), 160.3
(C-2Ј), 164.0 (C-4Ј), 190.4 (CϭO) ppm. C19H20O5 (328): calcd. C
69.50, H 6.14; found C 69.33, H 6.25.
hydroxy-2-iodobenzene. Under the same experimental con-
ditions as for the previous examples (Scheme 4), the reac-
tion afforded the protected chalcone 24 in 87% yield, thus
confirming the potential of aryl vinyl ketones as useful re-
agents in the Heck coupling reactions.
Conclusion
The results described herein confirm the versatility of this
new and efficient scheme for the synthesis of the flavonoid
skeleton and involves the use of a previously unexplored
reagent for the Heck coupling reaction. An aryl vinyl ke-
tone, such as 1, was successfully treated with a variety of
aryl iodides. In addition, we have shown that the use of a
different aryl vinyl ketone, such as 22, also gives satisfactory
yields. These reagents may be considered as interesting
starting materials for the design of various flavonoid deriva-
tives by their application in the palladium-catalysed Heck
reaction.
Deprotection of Chalcone 7: Chalcone 7 (104 mg, 0.32 mmol) and
EtSNa (4.04 mmol) in dry DMF (5 mL) were refluxed with stirring
under argon for about 4 h. After cooling, the reaction was
quenched by addition of 2 HCl in brine. Standard workup af-
forded 200 mg of crude material. The residue was purified by col-
umn chromatography on silica gel eluting with CHCl3/Et2O (6:4)
yielding 30 mg of compound 14 (30% yield), 7 mg of compound 15
(7% yield), 6 mg of compound 16 (7% yield), 5 mg of compound
17 (6% yield), 10 mg of compound 18 (11% yield), 25 mg of com-
pound 19 (27% yield) and 5 mg of compound 20 (5% yield). All of
the compounds isolated afforded satisfactory elemental analyses.
2,2Ј,4,4Ј-Tetramethoxychalcone (9): Reaction time: 5 h; 42 mg, 75%
yield.1H NMR (300 MHz, CDCl3): δ ϭ 3.83 (s, 3 H, OCH3), 3.85
(s, 6 H, 2 ϫ OCH3), 3.88 (s, 3 H, OCH3), 6.53Ϫ6.44 (m, 4 H, 3Ј-
H, 5Ј-H, 3-H, 5-H), 7.46 (d, J ϭ 16.2 Hz, 1 H, α-H), 7.53 (d, J ϭ
8.4 Hz, 1 H, 6-H), 7.71 (d, J ϭ 8.7 Hz, 1 H, 6Ј-H), 7.94 (d, J ϭ
16.2 Hz, 1 H, β-H) ppm.13C NMR (CDCl3): δ ϭ 55.7, 55.4 (2 ϫ
OCH3, 2 ϫ OCH3, C-2Ј, C-4Ј, C-2, C-4), 98.2 (C-3), 98.6 (C-3Ј),
104.8 (C-5), 105.2 (C-5Ј), 117.4 (C-1), 122.6 (C-1Ј), 125.3 (C-α),
130.1 (C-6), 132.4 (C-6Ј), 137.7 (C-β), 159.87 (C-4*), 159.89 (C-2*
), 162.4 (C-2Ј), 163.7 (C-4Ј), 191.0 (CϭO) ppm. C19H20O5 (328):
calcd. C 69.50, H 6.14; found C 69.42, H 6.33.
Experimental Section
General: NMR spectra were recorded with a Varian Mercury 300
spectrometer. NMR spectroscopic data marked with an asterisk
may be interchanged. Microanalyses were obtained using a Carlo-
Erba instrument. Mass spectra were measured using a Waters
Micro Q-TOF instrument. Chromatography was performed using
Merck Silica gel 60, which had been previously washed with 1
HCl, then water until the chlorine test was negative, activated at
120 °C for 48 h, then equilibrated with 10% of water. TLC 5 ϫ 20
cm plates Silica gel 60 F254 Merck. Reagents: Fluka. Solvents:
Carlo-Erba. All compounds were identified by NMR spectroscopy
and by comparison with literature data.[24]
Deprotection of Chalcone 9: Chalcone 9 (39 mg, 0.12 mmol) and
EtSNa (1.37 mmol) in dry DMF (1.5 mL) were refluxed with stir-
ring under argon for about 8 h. After cooling, the reaction was
quenched by addition of 2 HCl in brine. Standard workup af-
forded 74 mg of crude material. The residue was purified by col-
umn chromatography on silica gel eluting with CHCl3/Et2O (6:4)
yielding 10 mg (27% yield) of compound 13.
General Procedure for the Synthesis of Chalcones via Heck Coupling
Reaction: Equimolecular quantities of the aryl vinyl ketone 1 and
an aryl iodide were dissolved in acetonitrile, then Et3N (1.2 mL for
0.5 mmol), Pd(OAc)2 (2% mol) and PPh3 (5% mol) were added and
the mixture was refluxed (85 °C) with stirring under argon. The
reaction was complete after 2.5Ϫ10 h depending on the starting
materials. After completion, the reaction was quenched by addition
of ice and acidification with 1 HCl. Extraction with diethyl ether
and a standard workup gave the crude material, which was purified
by silica gel chromatography eluting with hexane/Et2O (6:4).
2,2Ј,4,4Ј,5-Pentamethoxychalcone (11): Reaction time: 6 h; 92 mg,
84% yield. 1H NMR (300 MHz, CDCl3): δ ϭ 3.85 (s, 6 H, 2 ϫ
OCH3), 3.87 (s, 6 H, 2 ϫ OCH3), 3.92 (s, 3 H, OCH3), 6.49 (d, J ϭ
2.1 Hz, 1 H, 3Ј-H), 6.54 (dd, J ϭ 2.1, J ϭ 8.4 Hz, 1 H, 5Ј-H), 7.09
(s, 1 H, 3-H), 7.26 (s, 1 H, 6-H), 7.38 (d, J ϭ 15.6 Hz, 1 H, α-H),
7.70 (d, J ϭ 8.4 Hz, 1 H, 6Ј-H), 7.95 (d, J ϭ 15.6 Hz, 1 H, β-H)
ppm. 13C NMR (CDCl3): δ ϭ 55.5, 55.7, 56.0, 56.4, 56.5 (5 ϫ
OCH3), 96.9 (C-3), 98.6 (C-3Ј), 104.9 (C-5Ј), 111.1 (C-6), 115.9
(C-1), 122.6 (C-1Ј), 125.2 (C-α), 132.4 (C-6Ј), 137.5 (C-β), 143.0
(C-5*), 151.8 (C-4*), 154.2 (C-2*), 159.9 (C-2Ј), 163.5 (C-4Ј), 191.0
(CϭO) ppm. C20H22O6 (358): calcd. C 67.03, H 6.19; found C
66.88, H 6.24.
2Ј,4,4Ј-Trimethoxychalcone (5): Reaction time: 5 h; 229 mg, 95%
yield. 1H NMR (300 MHz, CDCl3): δ ϭ 3.83 (s, 3 H, OCH3), 3.85
(s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.49 (d, J ϭ 2.1 Hz, 1 H, 3Ј-
H), 6.55 (dd, J ϭ 2.1, J ϭ 8.4 Hz, 1 H, 5Ј-H), 6.90 (d, J ϭ 8.7 Hz,
2 H, 3-H, 5-H), 7.38 (d, J ϭ 15.6 Hz, 1 H, α-H), 7.54 (d, J ϭ
8.7 Hz, 2 H, 2-H, 6-H), 7.65 (d, J ϭ 15.6 Hz, 1 H, β-H), 7.73 (d,
J ϭ 8.4 Hz, 1 H, 6Ј-H) ppm. 13C NMR (CDCl3): δ ϭ 55.7, 55.5,
55.3 (3 ϫ OCH3, C-2Ј, C-4Ј, C-4), 98.6 (C-3Ј), 105.0 (C-5Ј), 114.2
(C-3, C-5), 122.3 (C-1Ј), 124.9 (C-α), 128.0 (C-1), 129.8 (C-2, C-6),
132.5 (C-6Ј), 141.8 (C-β), 160.0 (C-4), 161.0 (C-2Ј), 163.7 (C-4Ј),
190.3 (CϭO) ppm. C18H18O4 (298): calcd. C 72.47, H 6.08; found
C 72.33, H 6.16.
2Ј,4Ј-Dimethoxychalcone (12): Reaction time: 4 h; 281 mg, 96%
yield. 1H NMR (300 MHz, CDCl3): δ ϭ 3.85 (s, 3 H, OCH3), 3.89
(s, 3 H, OCH3), 6.51 (d, J ϭ 2.2 Hz, 1 H, 3Ј-H), 6.57 (dd, J ϭ 2.2,
J ϭ 8.4 Hz, 1 H, 5Ј-H), 7.40Ϫ7.31 (m, 5 H, 2-H, 3-H, 4-H, 5-H,
6-H), 7.55 (d, J ϭ 15.8 Hz, 1 H, α-H), 7.72 (d, J ϭ 15.8 Hz, 1 H,
β-H), 7.79 (d, J ϭ 8.4 Hz, 1 H, 6Ј-H) ppm. 13C NMR (CDCl3):
δ ϭ 55.8, 55.6 (2 ϫ OCH3, C-2Ј, C-4Ј), 98.8 (C-3Ј), 105.5 (C-5Ј),
122.3 (C-1Ј), 127.4 (C-α), 128.5 (C-3, C-5), 128.9 (C-2, C-6), 130.0
2Ј,3,4,4Ј-Tetramethoxychalcone (7): Reaction time: 4.5 h; 260 mg,
80% yield.1H NMR (300 MHz, CDCl3): δ ϭ 3.84 (s, 3 H, OCH3), (C-4), 132.9 (C-6Ј), 135.6 (C-1), 142.0 (C-β), 160.6 (C-2Ј), 164.4 (C-
3.88 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 4Ј), 190.5 (CϭO) ppm. C17H16O3 (268): calcd. C 76.10, H 6.01;
6.48 (d, J ϭ 2.2 Hz, 1 H, 3Ј-H), 6.54 (dd, J ϭ 2.2, J ϭ 8.4 Hz, 1 found C 75.95, H 6.19.
Eur. J. Org. Chem. 2004, 2894Ϫ2898
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2897