Journal of Medicinal Chemistry
Article
3-Hydroxy-2-(4-bromophenyl)-chromen-4(1H)-one (2i). The syn-
thesis was performed according to the general procedure by using 1
(2.00 g, 14.7 mmol) and I (2.70 g, 14.7 mmol), affording 2i as a yellow
(CH3,Cym), 31.2 (CHCym), 77.9 (C3/C5Cym), 80.9 (C2/C6Cym), 95.9
(C4Cym), 98.9 (C1Cym), 117.8 (C8), 120.4 (C8a), 124.0 (C7), 124.5
(C5), 127.3 (C2′/C6′), 129.0 (C3′/C5′), 130.0 (C2), 132.6 (C6),
139.8 (C4′), 149.9 (C1′), 153.7 (C4a), 154.2 (C3), 183.1 (C4) ppm.
Elemental Anal. Calcd for C26H25ClO3Ru: C 59.82, H 4.83%. Found:
C 59.82, H 4.57%.
1
powder (2.31 g, 58%); mp 163−167 °C. H NMR (500.10 MHz,
DMSO-d6): δ = 7.47−7.50 (m, 1H, H7), 7.77−7.87 (m, H3′/H5′/
4
3
H6/H8), 8.12 (dd, J(H,H) = 1 Hz, J(H,H) = 8 Hz, 1H, H5), 8.19
(d, 3J(H,H) = 9 Hz, 2H, H2′/H6′), 9.85 (br s, 1H, OH) ppm.
13C{1H} NMR (125.75 MHz, DMSO-d6): δ = 118.9 (C8), 121.8
(C8a), 123.8 (C4′), 125.1 (C7), 125.3 (C5), 130.0 (C2), 132.1 (C3′/
C5′), 134.4 (C6), 139.9 (C1′), 144.5 (C3), 155.0 (C4a), 173.5 (C4)
ppm. Elemental Anal. Calcd for C15H9BrO3·0.1H2O: C 56.49, H
2.91%. Found: C 56.51, H 2.68%.
[Chlorido{3-(oxo-κO)-2-(4-fluorophenyl)-chromen-4(1H)-onato-
κO}(η6-p-cymene)ruthenium(II)] (3c). The reaction was performed
according to the general complexation procedure by using 2c (187 mg,
0.73 mmol), NaOMe (43 mg, 0.8 mmol), and [Ru(η6-p-cymene)Cl2]2
(200 mg, 0.33 mmol), affording 3c as red needles (230 mg, 66%); mp
1
235−236 °C (decomp). H NMR (500.10 MHz, CDCl3): δ = 1.40−
1.44 (m, 6H, CH3,Cym), 2.42 (s, 3H, CH3,Cym), 2.97−3.04 (m, 1H,
3-Hydroxy-2-(3-bromophenyl)-chromen-4(1H)-one (2j). The syn-
thesis was performed according to the general procedure by using 1
(2.00 g, 14.7 mmol) and j (2.70 g, 14.7 mmol), affording 2j as orange
CHCym), 5.40 (dd, 3J(H,H) = 5 Hz, 3J(H,H) = 5 Hz, 2H, H3/H5Cym),
3
3
5.66 (dd, J(H,H) = 5 Hz, J(H,H) = 5 Hz, 2H, H2/H6Cym), 7.15−
7.18 (m, 2H, H3′/H5′), 7.33−7.36 (m, 1H, H7), 7.54 (d, 3J(H,H) = 8
1
crystals (0.82 g, 18%); mp 165−167 °C. H NMR (500.10 MHz,
4
3
Hz, 1H, H8), 7.60−7.62 (m, 1H, H6), 8.22 (dd, J(H,H) = 1 Hz,
DMSO-d6): δ = 7.48−7.51 (m, 1H, H7), 7.56 (dd, J(H,H) = 8 Hz,
3J(H,H) = 8 Hz, 1H, H5′), 7.72−7.74 (m, 1H, H4′), 7.82−7.86 (m,
3J(H,H) = 8 Hz, 1H, H5), 8.61−8.64 (m, 2H, H2′/H6′) ppm.
13C{1H} NMR (125.75 MHz, CDCl3): δ = 18.7 (CH3,Cym), 22.5
(CH3,Cym), 31.3 (CHCym), 78.0 (C3/C5Cym), 81.0 (C2/C6Cym), 95.9
4
3
2H, H6/H8), 8.13 (dd, J(H,H) = 1 Hz, J(H,H) = 8 Hz, 1H, H5),
8.24−8.25 (m, 1H, H6′), 8.41−8.43 (m, 1H, H2′), 9.92 (br s, 1H,
OH) ppm. 13C{1H} NMR (125.75 MHz, DMSO-d6): δ = 119.0 (C8),
121.8 (C8a), 122.3 (C3′), 125.2 (C7), 125.3 (C5), 126.9 (C6′), 127.5
(C2′), 130.4 (C4′), 131.2 (C5′), 132.9 (C4′), 134.1 (C2), 134.4 (C6),
140.1 (C1′), 143.8 (C3), 155.1 (C4a), 173.6 (C4) ppm. Elemental
Anal. Calcd for C15H9BrO3: C 56.81, H 2.86%. Found: C 56.65, H
2.76%.
2
(C4Cym), 98.9 (C1Cym), 115.2 (d, J(C,F) = 21 Hz, C3′/C5′), 117.7
(C8), 120.1 (C8a), 124.1 (C7), 124.6 (C5), 128.8 (C2), 129.4 (d,
3J(C,F) = 8 Hz, C2′/C6′), 132.6 (C6), 148.4 (d, 4J(C,F) = 1 Hz, C1′),
1
153.8 (C4a), 154.1 (C3), 163.0 (d, J(C,F) = 251 Hz, C4′), 183.3
(C4) ppm. Elemental Anal. Calcd for C25H22ClFO3Ru: C 57.09, H
4.22%. Found: C 56.98, H 4.06%.
General Procedure for the Synthesis of the RuII(η6-p-
Cymene) Complexes 3a−3j. A solution of [Ru(η6-p-cymene)Cl2]2
(0.45 equiv) in dichloromethane (15 mL) was added to a solution of
3-hydroxyflavones 2a−j (1.00 equiv) and sodium methoxide (1.10
equiv) in methanol (15 mL). The reaction mixture was stirred at room
temperature and under argon atmosphere for 18 h. The solvent was
evaporated in vacuo, and the residue was extracted with dichloro-
methane, filtered, and concentrated. The pure product was obtained
by recrystallization from methanol.
[Chlorido{3-(oxo-κO)-2-(3-fluorophenyl)-chromen-4-onato-
κO}(η6-p-cymene)ruthenium(II)] (3d). The reaction was performed
according to the general complexation procedure by using 2d (187 mg,
0.73 mmol), NaOMe (43 mg, 0.8 mmol), and [Ru(η6-p-cymene)Cl2]2
(200 mg, 0.33 mmol), affording 3d as deep-red powder (180 mg,
51%); mp 210−212 °C (decomp). Single crystals suitable for X-ray
diffraction analysis were grown from CHCl3/n-hexane. 1H NMR
(500.10 MHz, CDCl3): δ = 1.40−1.46 (m, 6H, CH3,Cym), 2.42 (s, 3H,
3
CH3,Cym), 2.99−3.06 (m, 1H, CHCym), 5.40 (d, J(H,H) = 6 Hz, 2H,
[Chlorido{3-(oxo-κO)-2-phenyl-chromen-4(1H)-onato-κO}(η6-p-
cymene)ruthenium(II)] (3a). The reaction was performed according to
the general complexation procedure by using 2a (164 mg, 0.73 mmol),
NaOMe (43 mg, 0.8 mmol), and [Ru(η6-p-cymene)Cl2]2 (200 mg,
0.33 mmol) affording 3a as a deep-red powder (170 mg, 51%); mp
3
3
H3/H5Cym), 5.68 (dd, J(H,H) = 5 Hz, J(H,H) = 5 Hz, 2H, H2/
H6Cym), 7.08 (ddd, 4J(H,F) = 2 Hz, 3J(H,H) = 8 Hz, 3J(H,H) = 8 Hz,
1H, H4′), 7.33−7.36 (m, 1H, H7), 7.44 (ddd, 3J(H,F) = 6 Hz,
3J(H,H) = 8 Hz, 3J(H,H) = 8 Hz, 1H, H5′), 7.56 (d, 3J(H,H) = 8 Hz,
1H, H8), 7.61−7.65 (m, 1H, H6), 8.22 (dd, 4J(H,H) = 1 Hz, 3J(H,H)
1
229−230 °C (decomp). H NMR (500.10 MHz, CDCl3): δ = 1.41−
3
= 8 Hz, 1H, H5), 8.31 (d, J(H,H) = 8 Hz, 1H, H6′), 8.44−8.48 (m,
1.44 (m, 6H, CH3,Cym), 2.43 (s, 3H, CH3,Cym), 2.99−3.05 (m, 1H,
1H, H2′) ppm. 13C{1H} NMR (125.75 MHz, CDCl3): δ = 18.7
CHCym), 5.39 (dd, 3J(H,H) = 5 Hz, 3J(H,H) = 5 Hz, 2H, H3/H5Cym),
(CH3,Cym), 22.5 (2CH3,Cym), 31.3 (CHCym), 78.0 (C3/C5Cym), 80.0
3
3
5.67 (dd, J(H,H) = 5 Hz, J(H,H) = 5 Hz, 2H, H2/H6Cym), 7.33−
2
3
3
(C2/C6Cym), 95.9 (C4Cym), 99.0 (C1Cym), 114.1 (d, J(C,F) = 25 Hz,
7.35 (m, 1H, H7), 7.41 (dd, J(H,H) = 7 Hz, J(H,H) = 7 Hz, 1H,
C2′), 115.8 (d, 2J(C,F) = 22 Hz, C4′), 117.9 (C8), 119.9 (C8a), 122.5
H4′), 7.48 (dd, 3J(H,H) = 7 Hz, 3J(H,H) = 7 Hz, 2H, H3′/H5′), 7.57
4
3
(d, J(C,F) = 3 Hz, C6′), 124.2 (C7), 124.7 (C5), 127.2 (C2), 129.6
(d, J(H,H) = 8 Hz, 1H, H8), 7.59−7.61 (m, 1H, H6), 8.22 (dd,
3
3
(d, 3J(C,F) = 8 Hz, C5′), 132.9 (C6), 125.5 (d, 3J(C,F) = 9 Hz, C1′),
4J(H,H) = 1 Hz, J(H,H) = 8 Hz, 1H, H5), 8.61 (d, J(H,H) = 7 Hz,
1
153.9 (C4a), 154.9 (C3), 162.0 (d, J(C,F) = 243 Hz, C3′), 183.8
2H, H2′/H6′) ppm. 13C{1H} NMR (125.75 MHz, CDCl3): δ = 18.7
(CH3,Cym), 22.5 (CH3,Cym), 31.3 (CHCym), 78.0 (C3/C5Cym), 81.0
(C2/C6Cym), 95.9 (C4Cym), 98.9 (C1Cym), 117.9 (C8), 120.0 (C8a),
124.0 (C7), 124.6 (C5), 127.3 (C2′/C6′), 128.2 (C3′/C5′), 129.3
(C4′), 132.5 (C2), 132.6 (C6), 149.2 (C1′), 153.9 (C4a), 154.0 (C3),
183.3 (C4) ppm. Elemental Anal. Calcd for C25H23ClO3Ru: C 59.11,
H 4.56%. Found: C 59.04, H 4.39%.
(C4) ppm. Elemental Analysis Calcd for C25H22ClFO3Ru·0.25H2O: C
56.61, H 4.28%. Found: C 56.51, H 4.28%.
[Chlorido{3-(oxo-κO)-2-(2-fluorophenyl)-chromen-4-onato-
κO}(η6-p-cymene)ruthenium(II)] (3e). The reaction was performed
according to the general complexation procedure, by using 2e (187
mg, 0.73 mmol), NaOMe (43 mg, 0.8 mmol), and [Ru(η6-p-
cymene)Cl2]2 (200 mg, 0.33 mmol), affording 3e as red−brownish
powder (220 mg, 63%); mp 199−202 °C (decomp). 1H NMR
(500.10 MHz, CDCl3):): δ = 1.37−1.42 (m, 6H, CH3,Cym), 2.39 (s,
3H, CH3,Cym), 2.97−3.02 (m, 1H, CHCym), 5.36 (dd, 3J(H,H) = 6 Hz,
[Chlorido{3-(oxo-κO)-2-(4-methylphenyl)-chromen-4(1H)-onato-
κO}(η6-p-cymene)ruthenium(II)] (3b). The reaction was performed
according to the general complexation procedure by using 2b (184 mg,
0.73 mmol), NaOMe (43 mg, 0.8 mmol), and [Ru(η6-p-cymene)Cl2]2
(200 mg, 0.33 mmol), affording 3b as a red powder (240 mg, 68%).
Single crystals suitable for X-ray diffraction analysis were grown from
CHCl3/n-hexane; mp 235−236 °C (decomp). 1H NMR (500.10
MHz, CDCl3): δ = 1.40−1.43 (m, 6H, CH3,Cym), 2.42 (s, 3H,
CH3,Cym), 2.44 (s, 3H, CH3), 2.98−3.04 (m, 1H, CHCym), 5.38 (dd,
3J(H,H) = 5 Hz, 3J(H,H) = 5 Hz, 2H, H3/H5Cym), 5.65 (dd, 3J(H,H)
3
3J(H,H) = 6 Hz, 2H, H3/H5Cym), 5.68 (d, J(H,H) = 6 Hz, 2H, H2/
H6Cym), 7.14−7.19 (m, 1H, H3′), 7.21 (ddd, 4J(H,F) = 1 Hz, 3J(H,H)
= 8 Hz, 3J(H,H) = 8 Hz, 1H, H6′), 7.33−7.36 (m, 1H, H7), 7.38−7.42
(m, 1H, H4′), 7.51 (d, 3J(H,H) = 8 Hz, 1H, H8), 7.58−7.62 (m, 1H,
H6), 8.23 (dd, 4J(H,H) = 1 Hz, 3J(H,H) = 8 Hz, 1H, H5), 8.31 (ddd,
3
3
4J(H,F) = 1 Hz, J(H,H) = 7 Hz, J(H,H) = 7 Hz, 1H, H5′) ppm.
13C{1H} NMR (125.75 MHz, CDCl3): δ = 18.7 (CH3,Cym), 22.5
(2CH3,Cym), 31.2 (CHCym), 77.7 (C3/C5Cym), 81.2 (C2/C6Cym), 96.0
3
3
= 6 Hz, J(H,H) = 6 Hz, 2H, H2/H6Cym), 7.28 (d, J(H,H) = 9 Hz,
2H, H3′/H5′), 7.32−7.35 (m, 1H, H7), 7.55 (d, 3J(H,H) = 8 Hz, 1H,
H8), 7.58−7.61 (m, 1H, H6), 8.21 (dd, 4J(H,H) = 1 Hz, 3J(H,H) = 8
2
(C4cym), 98.9 (C1Cym), 116.3 (d, J(C,F) = 22 Hz, C3′), 118.3 (C8),
3
2
3
Hz, 1H, H5), 8.50 (d, J(H,H) = 8 Hz, 2H, H2′/H6′) ppm. 13C{1H}
120.1 (d, J(C,F) = 10 Hz, C1′), 120.1 (C8a), 123.6 (d, J(C,F) = 3
3
NMR (125.75 MHz, CDCl3): δ = 18.7 (CH3,Cym), 21.6 (CH3), 22.5
Hz, C6′), 124.1 (C7), 124.6 (C5), 131.1 (d, J(C,F) = 8 Hz, C4′),
10518
dx.doi.org/10.1021/jm301376a | J. Med. Chem. 2012, 55, 10512−10522