Synthesis of 7,8-diarylflavones by site-selective Suzuki-Miyaura reactions

Article abstract of DOI:10.1055/s-0030-1258043

7,8-Diarylflavones were prepared by Suzuki-Miyaura reactions of the bis(triflate) of 7,8-dihydroxyflavone. The first attack proceeded with very good site selectivity at position 7, due to steric and electronic reasons. Georg Thieme Verlag Stuttgart - New

Full text of DOI:10.1055/s-0030-1258043

2244
LETTER
Synthesis of 7,8-Diarylflavones by Site-Selective Suzuki–Miyaura Reactions
S
ynthesi
m
s
of 7,8-Diarylflavo
r
nes an Malik,a Munawar Hussain,a Nguyen Thai Hung,a Alexander Villinger,a Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
b
Received 3 February 2010
K3PO4 (1.5 equiv) as the base. The reactions were carried
out in 1,4-dioxane at 100 °C. GC-MS analysis of crude
product mixtures showed that less than 10% of monoad-
duct was present when the reactions were carried out un-
der the optimized conditions.
Abstract: 7,8-Diarylflavones were prepared by Suzuki–Miyaura
reactions of the bis(triflate) of 7,8-dihydroxyflavone. The first at-
tack proceeded with very good site selectivity at position 7, due to
steric and electronic reasons.
Key words: catalysis, palladium, Suzuki–Miyaura reaction, fla-
vones, regioselectivity
OH
OTf
HO
O
O
Ph
TfO
O
Ph
i
Flavones (2-arylchromones, 2-aryl-4H-1-benzopyran-4-
ones) are of considerable pharmacological relevance and
are widespread in nature as plant metabolites.1 Pharmaco-
logical activities include antioxidant, antimicrobial, anti-
inflammatory, antiproliferative, and vasculo-protective
O
1
2 (76%)
Scheme 1 Synthesis of 2. Reagents and conditions: (i) 1 (1.0 equiv),
activity.1–3 Most syntheses of flavones rely on the assem- Tf2O (2.4 equiv), pyridine (4.0 equiv), CH2Cl2, –78 °C to 0 °C, 4 h.
bly of the chromone core structure by conventional meth-
ods.2,3 The selective modification of naturally occurring
Ar
OTf
flavones is mainly limited to date to the O-alkylation and
Ar
O
Ph
TfO
O
Ph
acylation of hydroxy groups.2
i
ArB(OH)2
Polyhalogenated molecules represent interesting sub-
strates in palladium(0)-catalyzed cross-coupling reac-
tions.4 Recently, we have reported Suzuki–Miyaura and
Heck reactions of tetrabromothiophene, tetrabromo-N-
methylpyrrole, tetrabromoselenophene, and other polyha-
logenated heterocycles.5 We have also reported site-selec-
tive Suzuki–Miyaura reactions6 of the bis(triflate) of
3a–g
O
4a–g
O
2
Scheme 2 Synthesis of 4a–g. Reagents and conditions: (i), 2 (1.0
equiv), 3a–g (2.6 equiv), Pd(PPh3)4 (5 mol%), K3PO4 (4.0 equiv), 1,4-
dioxane, 100 °C, 4 h.
methyl 2,5-dihydroxybenzoate and related substrates.7 Table 1 Synthesis of 4a–g
Despite the great pharmacological importance of fla-
3
4
R
Yield of 4 (%)a
vones, only a few applications of palladium-catalyzed
cross-coupling reactions to flavone-derived halides or tri-
flates have been reported to date.8 Regioselective palladi-
um-catalyzed transformations of flavone-derived
bis(halides) or bis(triflates) have, to the best of our knowl-
edge, not yet been reported. Herein, we report the synthe-
sis of 7,8-diaryl-flavones by site-selective Suzuki–
Miyaura reactions of the bis(triflate) of 7,8-dihydroxyfla-
vone.
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
4e
4f
4g
4-EtC6H4
4-t-BuC6H4
4-ClC6H4
4-FC6H4
70
59
72
62
68
74
71
4-MeOC6H4
4-MeC6H4
3,5-Me2C6H3
Commercially available 7,8-dihydroxyflavone (1) was
transformed to its bis(triflate)
2 in good yield
(Scheme 1).9 The Suzuki–Miyaura reaction of 2 with aryl-
boronic acids 3a–g (2.6 equiv) afforded the 7,8-diarylfla-
vones 4a–g in 59–74% yield (Scheme 2, Table 1).10,11
Both electron-poor and electron-rich arylboronic acids
could be successfully employed. The best yields were ob-
tained using Pd(PPh3)4 (5 mol%) as the catalyst and
a Yields of isolated products.
The Suzuki–Miyaura reaction of 2 with arylboronic acids
3a,c,f,h,i (1.0 equiv) afforded the 7-aryl-8-trifluorosulfo-
nyloxy-flavones 5a–e in 66–76% yield with very good
site selectivity (Scheme 3, Table 2).10,12 During the opti-
mization, it proved to be important to use exactly 1.0
equivalent of the arylboronic acid and to carry out the
reaction at 70 °C instead of 100 °C. Both electron-poor
SYNLETT 2010, No. 15, pp 2244–2246
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258043; Art ID: D03510ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 7,8-Diarylflavones
2245
and electron-rich arylboronic acids were successfully structure of 4f was independently confirmed by X-ray
used. Some crude reaction mixtures were analyzed by crystal structure analysis (Figure 1).14
GC-MS. Besides the desired products 5, a small amount
of the corresponding bisadducts 4 were also present.
When the reaction was carried out at 100 °C, the amount
of bis-adduct was considerably higher compared to the sit-
uation when the reaction was carried out at 70 °C (<10%).
OTf
OTf
Ar
O
Ph
TfO
O
O
Ph
i
ArB(OH)2
3a,c,f,h,i
O
2
5a–e
Scheme 3 Synthesis of 5a–e. Reagents and conditions: (i) 2 (1.0
equiv), 3a,c,f,h,i (1.0 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (5 mol%),
1,4-dioxane, 70 °C, 4 h.
Figure 1 Crystal structure of 4f
Table 2 Synthesis of 5a–e
3
5
R
Yield of 5 (%)a
The site-selective formation of 5a–e can be explained
with steric and electronic arguments. The first attack of
palladium(0)-catalyzed cross-coupling reactions general-
ly occurs at the more electronical deficient and sterically
less hindered position.4,15 Position 7 of 2 is sterically less
hindered than position 8. In addition, position 7 (located
meta to the ether oxygen atom and para to the carbonyl
group) is considerably more electron-deficient than posi-
tion 1 (located ortho to the ether oxygen atom and meta to
the carbonyl group).
3a
3c
3f
3h
3i
5a
5b
5c
5d
5e
4-EtC6H4
4-ClC6H4
4-MeC6H4
4-F3CC6H4
4-HC=CH2C6H4
72
66
76
69
74
a Yields of isolated products.
In conclusion, we have reported an efficient synthesis of
7,8-diarylflavones were prepared by Suzuki–Miyaura
reactions of the bis(triflate) of 7,8-dihydroxyflavone. The
first attack proceeded with very good site selectivity at po-
sition 7.
The Suzuki–Miyaura reaction of 5c and 5b with aryl-
boronic acids 3a and 3e (1.3 equiv) afforded the 7,8-di-
arylflavones 6a and 6b, respectively (Scheme 4,
Table 3).10,13 The reactions were carried out at 100 °C.
Ar2
OTf
Acknowledgment
Ar1
O
O
Ph
Ar1
O
O
Ph
i
Financial support by the State of Pakistan (HEC scholarships for
I.M. and M.H.), by the State of Mecklenburg-Vorpommern (schol-
arships for M.H. and N.T.H.) and by the DAAD (scholarships for
I.M. and N.T.H.) is gratefully acknowledged.
Ar2B(OH)2
3a,e
5b,c
6a,b
Scheme 4 Synthesis of 6a,b. Reagents and conditions: (i) 5b,c (1.0
equiv), 3a,e (1.3 equiv), K3PO4 (1.5 equiv), Pd(PPh3)4 (5 mol%), 1,4-
dioxane, 100 °C, 4 h.
References and Notes
(1) (a) Römpp Lexikon Naturstoffe; Steglich, W.; Fugmann, B.;
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
(b) Harborne, J. B.; Baxter, H. The Handbook of Natural
Flavonoids, Vol. 1; John Wiley and Sons: Chichester, 1999.
(c) Beecker, G. R. J. Nutr. 2003, 133, 3248S. (d) Havsteen,
B. H. Pharmacol. Ther. 2002, 96, 67. (e) Middleton, E. Jr.;
Kandaswami, C.; Theoharides, T. C. Pharmacol. Rev. 2000,
52, 672.
Table 3 Synthesis of 7,8-Diarylflavones 6a,b
3
5
6
Ar1
4-MeC6H4 4-EtC6H4
4-ClC6H4 4-MeOC6H4
Ar2
Yield of 6 (%)a
3a
3e
5c
5b
6a
6b
66
73
(2) (a) Daskiewies, J.; Depeint, F.; Viornery, L.; Bayet, C.;
Geraldine, C.; Comte, G.; Gee, J.; Johnson, I.; Ndjoko, K.;
Hostettmann, K.; Barron, D. J. Med. Chem. 2005, 48, 2790.
(b) Rao, Y. K.; Fang, S. H.; Tzeng, Y. M. Bioorg. Med.
Chem. 2005, 13, 6850. (c) Wang, S. F.; Jiang, Q.; Ye, Y. H.;
Li, Y.; Tan, R. X. Bioorg. Med. Chem. 2005, 13, 4880.
(d) Gao, H.; Kawabata, J. Bioorg. Med. Chem. 2005, 13,
1661. (e) Gao, G. Y.; Li, D. J.; Keung, W. M. J. Med. Chem.
2001, 44, 3320.
a Yields of isolated products.
All products were characterized by spectroscopic meth-
ods. The constitution of products 5a–e and 6a,b were
proved by 2D NMR experiments (HMBC, NOESY). The
Synlett 2010, No. 15, 2244–2246 © Thieme Stuttgart · New York

2246
I. Malik et al.
LETTER
(3) (a) Su, B.; Hackett, J. C.; Diaz-Cruz, E. S.; Kim, Y. W.;
Brueggemeier, R. W. Bioorg. Med. Chem. 2005, 13, 6571.
(b) Kim, Y. W.; Hackett, J. C.; Brueggemeier, R. W. J. Med.
Chem. 2004, 47, 4032. (c) Traxler, P.; Green, J.; Mett, H.;
Sequin, U.; Furet, P. J. Med. Chem. 1999, 42, 1018.
(d) Cushman, M.; Zhu, H.; Geahlen, R. L.; Kraker, A. J.
J. Med. Chem. 1994, 37, 3353.
(4) For reviews of cross-coupling reactions of polyhalogenated
heterocycles, see: (a) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Schnürch, M.; Flasik, R.;
Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur.
J. Org. Chem. 2006, 3283.
(5) (a) Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer,
P. Tetrahedron Lett. 2008, 49, 1698. (b) Dang, T. T.;
Villinger, A.; Langer, P. Adv. Synth. Catal. 2008, 350, 2109.
(c) Hussain, M.; Nguyen, T. H.; Langer, P. Tetrahedron Lett.
2009, 50, 3929. (d) Tengho Toguem, S.-M.; Hussain, M.;
Malik, I.; Villinger, A.; Langer, P. Tetrahedron Lett. 2009,
50, 4962. (e) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger,
A.; Langer, P. Adv. Synth. Catal. 2009, 351, 1595.
(6) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
isolated as a crystalline light yellow solid (148 mg, 74%),
mp 248–249 °C. 1H NMR (300 MHz, CDCl3): d = 2.19 (s, 3
H, CH3), 2.29 (s, 3 H, CH3), 6.75 (s, 1 H), 6.90–7.04 (m, 8
H, ArH), 7.24–7.33 (m, 3 H, ArH), 7.39 (d, 1 H, J = 8.2 Hz,
ArH), 7.48–7.51 (m, 2 H, ArH), 8.16 (d, 1 H, J = 8.2 Hz,
ArH). 13C NMR (75MHz, CDCl3): d = 21.2, 21.4 (CH3),
106.7 (CH), 122.8 (C), 124.4, 126.2, 127.4, 128.6, 128.7,
128.9, 129.7 (CH), 130.2 (C), 131.0, 131.4 (CH), 131.6,
131.7, 137.0, 137.1, 146.7, 153.9, 163.2, 178.6 (C). IR
(KBr): n = 2917 (w), 1631 (m), 1592 (w), 1446, 1371 (m),
1238 (w), 1145, 1016 (m), 917 (w), 816, 773, 690 (s), 665
(m) cm–1. GC-MS (EI, 70 eV): m/z (%) = 402 (100) [M+],
387 (34), 359 (3), 331 (4), 299 (4), 285 (7), 243 (9), 229 (12).
HRMS (EI): m/z calcd for C29H22O2 [M+]: 402.16143; found:
402.161442.
(12) 7-(4-Ethylphenyl)-4-oxo-2-phenyl-4H-chromen-8-yl
Trifluoromethanesulfonate (5a)
Starting with 2 (156 mg, 0.30 mmol), K3PO4 (96 mg, 0.45
mmol), Pd(PPh3)4 (5 mol%), (4-ethylphenyl)boronic acid
(3a, 45 mg, 0.30 mmol), and 1,4-dioxane (3mL), 5a was
isolated as a white solid (102 mg, 72%), mp 167–168 °C. 1H
NMR (500 MHz, CDCl3): d = 1.22 (t, 3 H, J = 7.7 Hz, CH3),
2.66 (q, 2 H, J = 7.5 Hz, CH2), 6.83 (s, 1 H), 7.27 (d, 2 H,
J = 8.0 Hz, ArH), 7.38 (d, 2 H, J = 8.3 Hz, ArH), 7.44 (d, 1
H, J = 8.3 Hz, ArH), 7.46–7.50 (m, 3 H, ArH), 7.95–7.97 (m,
2 H, ArH), 8.18 (d, 1 H, J = 8.3 Hz, ArH). 13C NMR (125.76
MHz, CDCl3): d = 15.5 (CH3), 28.7 (CH2), 108.2 (CH),
118.0 (q, JF,C = 320 Hz, CF3), 124.2 (C), 125.1, 126.7, 127.4,
128.3, 129.1, 129.2 (CH), 130.8, 131.6 (C), 132.1 (CH),
135.1, 140.7, 145.9, 149.0, 163.8, 176.7 (C). 19F NMR (282
MHz, CDCl3): d = –74.3. IR (KBr): n = 2916, 2850 (w),
1622, 1568, 1447 (m), 1386 (s), 1271 (m), 1164 (s), 1041
(m), 906 (w), 811, 767, 681 (s), 634 (w) cm–1. GC-MS (EI,
70 eV): m/z (%) = 474 (40) [M+], 410 (28), 395 (18), 366 (3),
341 (100), 326 (8), 313 (20), 281 (4). HRMS (EI): m/z calcd
for C24H17F3O5S [M+]: 474.07471; found: 474.07492.
(13) 8-(4-Ethylphenyl)-2-phenyl-7-(p-tolyl)-4H-chromen-4-
one (6a)
(7) Nawaz, M.; Ibad, M. F.; Obaid-Ur-Rahman, A.; Khera,
R. A.; Villinger, A.; Langer, P. Synlett 2010, 150.
(8) (a) Zembower, D.; Zhang, H. J. Org. Chem. 1998, 63, 9300.
(b) Zheng, X.; Meng, W.; Qing, F. Tetrahedron Lett. 2004,
45, 8083. (c) Huang, X.; Tang, E.; Xu, W. M.; Cao, J.
J. Comb. Chem. 2005, 7, 802. (d) Peng, W.-J.; Han, X.-W.;
Yu, B. Chin. J. Chem. 2006, 24, 1154.
(9) Synthesis of 4-Oxo-2-phenyl-4H-chromene-7,8-diyl-
bis(trifluoromethanesulfonate (2)
To a CH2Cl2 solution (10 mL) of 1 (254 mg, 1.0 mmol) was
added pyridine (0.32 mL, 4.0 mmol) at –78 °C under argon
atmosphere. After stirring for 10 min, Tf2O (0.40 mL, 2.4
mmol) was added at –78 °C. The mixture was allowed to
warm to 0 °C and stirred for 4 h. The reaction mixture was
filtered, and the filtrate was concentrated in vacuo. Product
2 was isolated by rapid column chromatography (flash silica
gel, heptanes–EtOAc) as a white solid (393 mg, 76%), mp
142–143 °C. 1H NMR (300 MHz, CDCl3): d = 6.82 (s, 1 H),
7.43–7.52 (m, 4 H, ArH), 7.88–7.91 (m, 2 H, ArH), 8.25 (d,
J = 9.4 Hz, 1 H). 13C NMR (75.5 MHz, CDCl3): d = 108.3
(CH), 118.6 (q, JF,C = 321.6 Hz, CF3), 118.7 (q, JF,C = 320.4
Hz, CF3), 118.9 (CH), 124.7 (C), 126.6, 126.7, 129.3 (CH),
129.9, 130.2 (C), 132.6 (CH), 143.9, 149.5, 164.5, 175.3 (C).
19F NMR (282 MHz, CDCl3): d = –72.66, –72.85. IR (KBr):
n = 3080 (w), 1660 (s), 1613 (m), 1427 (s), 1359 (m), 1210,
1126 (s), 1053, 996, 955, 836, 794, 756 (m), 733 (w), 684
(m) cm–1. GC-MS (EI, 70 eV): m/z (%) = 518 (95) [M+], 385
(7), 357 (15), 321 (29), 293 (100), 219 (66), 191 (79). HRMS
(EI, 70 eV): m/z calcd for C17H8F6O8S2 [M+]: 517.95700;
found: 517.95651.
Following the general procedure starting with 5c (101 mg,
0.22 mmol), K3PO4 (93 mg, 0.44 mmol), Pd(PPh3)4 (5
mol%), 4-(ethylphenyl)boronic acid (3a, 44 mg, 0.29
mmol), and 1,4-dioxane (3 mL), 6a was isolated as a yellow
solid (60 mg, 66%), mp 198–199 °C. 1H NMR (500 MHz,
CDCl3): d = 1.20 (t, 3 H, J = 7.9 Hz, CH3), 2.23 (s, 3 H,
CH3), 2.62 (q, 2 H, J = 7.5 Hz), 6.79 (s, 1 H), 6.95–7.01 (m,
4 H, ArH), 7.07–7.12 (m, 4 H, ArH), 7.26–7.38 (m, 3 H,
ArH), 7.43 (dd, 1 H, J = 3.4, 8.3 Hz, ArH), 7.50–7.54 (m, 2
H, ArH), 8.18 (d, 1 H, J = 8.3 Hz, ArH). 13C NMR (125.75
MHz, CDCl3): d = 15.8, 21.1 (CH3), 28.7 (CH2), 122.8 (C),
124.3, 126.2, 127.4, 128.6, 128.7, 128.8, 128.9, 129.6,
131.0, 131.3 (CH), 131.6, 131.7, 132.0, 137.0, 143.5, 146.5,
146.7, 153.9, 136.1, 178.7 (C). IR (KBr): n = 2962, 2923,
1644 (s), 1597 (w), 1371 (m), 1202, 1096, 1016 (w), 815,
771 (m), 688 (w) cm–1. GC-MS (EI, 70 eV): m/z (%) = 416
(100) [M+], 402 (16), 387 (49), 313 (6), 285 (14), 271 (5),
253 (6), 239 (9). HRMS (EI): m/z calcd for C30H24O2 [M+]:
416.17783; found: 416.17762.
(10) General Procedure for Suzuki–Miyaura Cross-Coupling
Reactions
A 1,4-dioxane solution (3–4 mL) of 2 (1.0 equiv),
arylboronic acid 3 (1.0–1.3 equiv per desired cross-coupling
reaction), K3PO4 (1.5–2.0 equiv per desired cross-coupling
reaction), and Pd(PPh3)4 (5 mol%) was heated at 70–100 °C
for 4 h. After cooling to 20 °C, a sat. aq solution of NH4Cl
was added, the organic and aqueous layers were separated,
and the latter was extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4), filtered, and the filtrate
was concentrated in vacuo. The residue was purified by
column chromatography.
(14) CCDC-781627 contains all crystallographic details of
this publication and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road,
GB-Cambridge CB21EZ; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk.
(11) 2-Phenyl-7,8-di(p-tolyl)-4H-chromen-4-one (4f)
Starting with 2 (259 mg, 0.5 mmol), K3PO4 (424 mg, 2.0
mmol), Pd(PPh3)4 (5 mol%), 4-methylphenylboronic acid
(3f, 177 mg, 1.3 mmol), and 1,4-dioxane (5 mL), 4f was
(15) For a simple guide for the prediction of the site-selectivity of
palladium(0)-catalyzed cross-coupling reactions based on
the 1H NMR chemical shift values, see: Handy, S. T.; Zhang,
Y. Chem. Commun. 2006, 299.
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