References and Notes
- 1
Havsteen BH.
Pharmacol. Ther.
2002,
96:
67
-
2a
Birt DF.
Hendrich S.
Wang W.
Pharmacol. Ther.
2001,
90:
157 ; and references therein
-
2b
López-Lázaro M.
Curr. Med. Chem.: Anti-Cancer Agents
2002,
2:
691 ; and references therein
-
2c
Pouget C.
Lauthier F.
Simon A.
Fagnere C.
Basly J.-P.
Delage C.
Chulia A.-J.
Bioorg. Med. Chem. Lett.
2001,
11:
3095
-
2d
Zheng X.
Meng WD.
Xu YY.
Cao JG.
Qing FL.
Bioorg. Med. Chem. Lett.
2003,
13:
881
- 3
Gobbi S.
Rampa A.
Bisi A.
Belluti F.
Piazzi L.
Valenti P.
Caputo A.
Zampiron A.
Carrara M.
J. Med. Chem.
2003,
46:
3662 ; and references therein
- 4
Atassi G.
Briet P.
Berthelon JJ.
Collonges F.
Eur. J. Med. Chem.
1985,
20:
393
-
5a
Yu D.
Chen CH.
Brossi A.
Lee KH.
J. Med. Chem.
2004,
47:
4072 ; and references therein
-
5b
Hu C.
Chen K.
Shi Q.
Kilkuskie RE.
Chen Y.
Lee KH.
J. Nat. Prod.
1994,
57:
42
-
5c
Ungwitayatorn J.
Samee W.
Pimthon J.
J. Mol. Struct.
2004,
689:
99
-
6a
Burda S.
Oleszek W.
J. Agric. Food Chem.
2001,
49:
2774 ; and references therein
-
6b
Rackova L.
Firakova S.
Kostalova D.
Stefek M.
Sturdik E.
Majekova M.
Bioorg. Med. Chem.
2005,
13:
6477
-
6c
Soobrattee MA.
Neergheen VS.
Luximon-Ramma A.
Aruoma OI.
Bahorun T.
Mutation Res.
2005,
579:
200
- 7
Klymchenko AS.
Mély Y.
Tetrahedron Lett.
2004,
45:
8391 ; and references therein
- 8
Horton DA.
Bourne GT.
Smythe ML.
Chem. Rev.
2003,
103:
893
-
10a
Braña MF.
Morán M.
Emling F.
Schlick E.
Drug Des. Discov.
1994,
11:
329
-
10b
Mazumdar AKD.
Karmakar PK.
J. Indian Chem. Soc.
1990,
67:
911
-
10c
Banerji KD.
Poddar D.
J. Indian Chem. Soc.
1976,
53:
1119
-
10d
Banerji KD.
Poddar D.
J. Indian Chem. Soc.
1979,
56:
62
-
11a
de Meijere A.
Meyer FE.
Angew. Chem., Int. Ed. Engl.
1994,
33:
2379 ; and references therein
-
11b
Reetz MT.
Lohmer G.
Schwickardi R.
Angew. Chem. Int. Ed.
1998,
37:
481
- 12
Espinet P.
Echavarren AM.
Angew. Chem. Int. Ed.
2004,
43:
4704 ; and references therein
-
13a
Beletskaya IP.
Cheprakov AV.
Chem. Rev.
2000,
100:
3009 ; and references therein
-
13b
Davies SG.
Mobbs BE.
Goodwin CJ.
J. Chem. Soc., Perkin Trans. 1
1987,
2597
-
16a
Littke AF.
Fu GC.
Angew. Chem. Int. Ed.
2002,
41:
4176 ; and references therein
-
16b
Littke AF.
Schwarz L.
Fu GC.
J. Am. Chem. Soc.
2002,
124:
6343
- 20
Littke AF.
Fu GC.
J. Org. Chem.
1999,
64:
10
- 21
Demeyer N.
Haemers A.
Mishra L.
Pandey HK.
Pieters LAC.
Vandenberghe DA.
Vlietinck AJ.
J. Med. Chem.
1991,
34:
736
-
22a
Pal M.
Dakarapu R.
Parasuraman K.
Subramanian V.
Yeleswarapu KR.
J. Org. Chem.
2005,
70:
7179 ; and references therein
-
22b
Pal M.
Parasuraman K.
Subramanian V.
Dakarapu R.
Yeleswarapu KR.
Tetrahedron Lett.
2004,
45:
2305
-
22c
Pal M.
Subramanian V.
Parasuraman K.
Yeleswarapu KR.
Tetrahedron
2003,
59:
9563
-
22d
Larock RC.
Tian QP.
J. Org. Chem.
1998,
63:
2002
- 23
Joo YH.
Kim JK.
Kang SH.
Noh MS.
Ha JY.
Choi JK.
Lim KM.
Lee CH.
Chung S.
Bioorg. Med. Chem. Lett.
2003,
13:
413
- 24
Echavarren AM.
Stille JK.
J. Am. Chem. Soc.
1987,
109:
5478
-
25a
Dounay AB.
Overman LE.
Chem. Rev.
2003,
103:
2945
-
25b
Crisp GT.
Glink PT.
Tetrahedron
1992,
48:
3541
-
25c
Cabri W.
Candiani I.
Bedeschi A.
Santi R.
J. Org. Chem.
1992,
57:
3558
-
25d
Cabri W.
Candiani I.
Debernardinis S.
Francalanci F.
Penco S.
Santi R.
J. Org. Chem.
1991,
56:
5796
- 26
Utale PS.
Raghuwanshi PB.
Doshi AG.
Asian J. Chem.
1999,
11:
644
9 All compounds reported herein gave spectral data consistent with the assigned structures as well as satisfactory elemental analyses.
14
General Procedure for the Heck Reaction in Position 8 - Synthesis of 6-Chloro-8-(2-methoxycarbonylethenyl)-flavone (4).
A solution of 2 (150 mg, 0.45 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), Pd(o-tolyl)3 (30 mg, 0.9 mmol), Et3N (0.12 mL, 0.9 mmol) and methyl acrylate (0.08 mL, 0.9 mmol) in DMF (4 mL) in a microwave tube was heated in a microwave cavity for 30 min at 160 °C. The solution was filtered through Celite® and H2O (10 mL) was added. The mixture was extracted with CH2Cl2 (4 × 10 mL). The combined organic phases were dried over anhyd Na2SO4 before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to afford 133 mg (87%) of 4 as a light-yellow powder; mp 181-182 °C. 1H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3 H), 6.66 (d, J = 16.1 Hz, 1 H), 6.84 (s, 1 H), 7.56-7.59 (m, 3 H), 7.86 (d, J = 2.6 Hz, 1 H), 7.90-7.92 (m, 2 H), 8.21 (d, J = 2.6 Hz, 1 H), 8.21 (d, J = 16.1 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 52.3, 108.0, 122.7, 125.7, 126.6, 126.8, 127.1, 129.6, 131.4, 131.5, 131.8, 132.3, 135.7, 152.5, 163.9, 166.7, 176.9. Anal. Calcd for C19H13ClO4: C, 66.97, H, 3.85. Found: C, 66.82, H, 3.77.
15
General Procedure for Stille Coupling in Positions 3 and 8 - Synthesis of 8-Allyl-6-chloro-flavone (3).
A solution of 2 (400 mg, 1.2 mmol), Pd(PPh3)4 (140 mg, 0.12 mmol) and allyltributyltin (600 mg, 1.8 mmol) in dioxane (30 mL) under N2 was warmed to 80 °C for 14 h. The mixture was allowed to cool to r.t. and filtered through Celite®. A sat. aq KF solution (15 mL) was added and stirred for 30 min. The solution was extracted with CH2Cl2 (4 × 30 mL). The combined organic phases were washed with H2O (2 × 10 mL), dried over anhyd MgSO4 before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using CH2Cl2 as eluent to afford 282 mg (79%) of 3 as a white powder; mp 127-128 °C. 1H NMR (400 MHz, CDCl3): δ = 3.74 (d, J = 6.6 Hz, 2 H), 5.19-5.25 (m, 2 H), 6.01-6.12 (m, 1 H), 6.83 (s, 1 H), 7.50 (d, J = 2.6 Hz, 1 H), 7.54-7.57 (m, 3 H), 7.89-7.91 (m, 2 H), 8.07 (d, J = 2.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 33.9, 107.5, 118.1, 123.4, 125.1, 126.4, 129.4, 131.1, 131.8, 132.0, 134.2, 134.5, 152.8, 163.4, 177.6. Anal. Calcd for C18H13ClO2: C, 72.85, H, 4.42. Found: C, 72.67, H, 4.35.
17
General Procedure for the Stille Coupling in Position 6 - Synthesis of 6,8-Diallyl-flavone (5).
A solution of 3 (51 mg, 0.17 mmol), allyltributyltin (85 mg, 0.26 mmol), Pd2(dba)3 (10 mg, 0.01 mmol) and P(t-Bu)3 (8 mg, 0.04 mmol) in dioxane (15 mL) under N2 was warmed to 80 °C for 14 h. The mixture was allowed to cool to r.t. and filtered through Celite®. A sat. aq KF solution (10 mL) was added and stirred for 30 min. The solution was extracted with CH2Cl2 (4 × 20 mL). The combined organic phases were washed with H2O (2 × 10 mL), dried over anhyd MgSO4 before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using a manual gradient of CH2Cl2-Et2O (100:0 to 95:5) as eluent to afford 12 mg (22%) of 5 as light crystals; mp 86-87 °C. 1H NMR (400 MHz, CDCl3): δ = 3.48 (d, J = 6.4 Hz, 2 H), 3.75 (d, J = 6.8 Hz, 2 H), 5.10-5.19 (m, 4 H), 5.94-6.14 (m, 2 H), 6.84 (s, 1 H), 7.39 (d, J = 2.2 Hz, 1 H), 7.52-7.55 (m, 3 H), 7.91-7.94 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 34.3, 39.9, 107.6, 116.8, 117.2, 123.3, 124.1, 126.5, 129.3, 129.7, 131.8, 132.3, 135.0, 135.6, 136.8, 137.2, 137.3, 163.2, 179.0. Anal. Calcd for (C21H18O2)2·H2O: C, 81.00, H, 6.15. Found: C, 80.78, H, 5.86.
18 According to NMR spectroscopy the major side products showed a Pd-mediated rearrangement of the double bond in the allyl group with or without a concomitant Stille coupling in position 6.
19
General Procedure for the Heck Reaction in Position 6 - Synthesis of 6,8-Bis(2-methoxycarbonylethenyl)-flavone (6).
Et3N (0.04 mL, 0.26 mmol) was added to a suspension of 4 (46 mg, 0.13 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), methyl acrylate (0.03 mL, 0.33 mmol) and [P(t-Bu)3H]BF4 (12 mg, 0.04 mmol) in dioxane (4 mL) under N2 in a microwave tube. The mixture was heated in a microwave cavity for 30 min at 160 °C. The solution was filtered through Celite® and H2O (10 mL) was added. The mixture was extracted with CH2Cl2 (4 × 10 mL). The combined organic phases were dried over anhyd MgSO4 before the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using a manual gradient of CH2Cl2-Et2O (100:0 to 95:5) as eluent to afford 40 mg (79%) of 6 as a white powder; mp 214-215 °C. 1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 3.87 (s, 3 H), 6.56 (d, J = 15.9 Hz, 1 H), 6.71 (d, J = 16.4 Hz, 1 H), 6.85 (s, 1 H), 7.56-7.58 (m, 3 H), 7.73 (d, J = 15.9 Hz, 1 H), 7.90-7.93 (m, 2 H), 8.01 (d, J = 2.2 Hz, 1 H), 8.24 (d, J = 16.4 Hz, 1 H), 8.39 (d, J = 2.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 52.0, 52.2, 108.1, 120.2, 122.2, 124.8, 125.6, 126.5, 127.0, 129.5, 131.0, 131.3, 131.6, 132.2, 136.3, 142.3, 154.6, 163.7, 166.8, 166.9, 177.4. Anal. Calcd for C23H18O6: C, 70.76, H, 4.65. Found: C, 70.59, H, 4.74.
27
8-Bromo-6-chloro-3-[3-(
N
-phthalimido)propoxy]-flavone (13).
A solution of 8 (6.2 g, 17.7 mmol), N-(3-bromo-propyl)phthalimide (9.5 g, 35.4 mmol) and K2CO3 (4.5 g, 35.4 mmol) in DMF (50 mL) was stirred at 50 °C for 15 h. The mixture was allowed to cool and H2O was added. The solution was acidified with HCl (1 M). The precipitate was filtered off and the solid was recrystallized from EtOH to afford 8.5 g (87%) of 13 as white crystals; mp 185-186 °C. 1H NMR (400 MHz, CDCl3): δ = 2.10-2.17 (m, 2 H), 3.83 (t, J = 7.0 Hz, 2 H), 4.18 (t, J = 6.2 Hz, 2 H), 7.52-7.58 (m, 3 H), 7.70-7.72 (m, 2 H), 7.83-7.85 (m, 2 H), 7.88 (d, J = 1.3 Hz, 1 H), 8.14 (d, J = 1.3 Hz, 1 H), 8.23-8.25 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 29.5, 53.5, 70.5, 112.9, 123.4, 124.8, 125.8, 128.9, 129.1, 130.5, 130.9, 131.5, 132.3, 134.1, 136.6, 140.7, 150.5, 156.2, 168.4, 173.5. Anal. Calcd for C26H17BrClNO5: C, 57.96, H, 3.18, N, 2.60. Found: C, 57.79, H, 3.07, N, 2.48.
