Synthesis of gem-difluoromethylenated biflavonoid via the Suzuki coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2004.08.180

gem-Difluoromethylenated biflavonoid 1 was synthesized via the Suzuki coupling reaction. The key intermediate 6-iodonated flavone 4 was regioselectively synthesized by the use of AgOAc/I₂ under mild conditions without handling of a strongly toxic reagent. The key step was the formation of a flavone 3′-boronate 3 using a palladium-catalyzed exchange of the corresponding 3′-iodonated flavone with a diboron reagent.

Full text of DOI:10.1016/j.tetlet.2004.08.180

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8083–8085
Synthesis of gem-difluoromethylenated biflavonoid via the
Suzuki coupling reaction
Xing Zheng,a Wei-Dong Menga and Feng-Ling Qinga,b,
*
aCollege of Chemistry and Chemical Engineering, Donghua University, 1882 West Yanan Lu, Shanghai 200051, China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 9 July 2004;revised 25 August 2004;accepted 26 August 2004
Available online 21 September 2004
Abstract—gem-Difluoromethylenated biflavonoid 1 was synthesized via the Suzuki coupling reaction. The key intermediate 6-iodo-
nated flavone 4 was regioselectively synthesized by the use of AgOAc/I2 under mild conditions without handling of a strongly toxic
reagent. The key step was the formation of a flavone 30-boronate 3 using a palladium-catalyzed exchange of the corresponding 30-
iodonated flavone with a diboron reagent.
Ó 2004 Elsevier Ltd. All rights reserved.
Biflavonoids are a group of naturally occurring com-
HCF2O
pounds and possess a broad range of pharmacological
properties including anti-oxidant, anti-microbial, anti-
inflammatory and anti-cancer properties.1–3 However,
the anti-cancer activity of biflavonoids is low. It is
known that fluorine is the most electronegative element
and the van der Waals radius of fluorine is close to that
of hydrogen. The introduction of the trifluoromethyl
(CF3) or gem-difluoromethylene (CF2) group into
organic molecules often changes their physiological,
physical and chemical properties dramatically, without
extra steric demand. We have recently reported that
introduction of CF3 group into flavonoids molecule
can enhance their anti-cancer activities.4,5 Despite the
wide occurrence and biological importance of biflavo-
noids, synthetic efforts towards efficient preparation of
fluorinated biflavonoids are rarely reported. As a part
of our current work on the search for anti-cancer sub-
stances with high efficacy, low toxicity and minimum
of side effects, we describe herein the synthesis of gem-
difluoromethylenated biflavonoid 1.
O
O
B
OMe
MeO
O
O
O
3
OMe
O
HCF2O
OMe
+
OCF2H
HF2CO
I
O
O
MeO
2
1
OMe
O
O
Scheme 1. Retrosynthetic analysis.
Compound 2 was prepared as outlined in Scheme 2.
Condensation of phloroglucinol with chloroacetonitrile
catalyzed by ZnCl2 and HCl gas followed by hydrolysis
provided ketone 7 in 65% yield. Treatment of 7 with p-
hydroxytolualdehyde in the presence of excess NaOH in
H2O/EtOH and followed by acidification with aqueous
HCl gave the expected compound 6 in 92% yield.6 Based
on our knowledge of the chemistry of flavonoids, the
5-hydroxy group of 6 was hydrogen bonded to the
adjacent carbonyl group, and thus not readily gem-
difluoromethylenated.7 Chemoselective 40-O- and 7-O-
gem-difluoromethylenation of 6 was therefore readily
achieved using HCF2Cl gas in the presence of NaOH
We envisaged that 1 could be constructed from 6-iodo-
flavone 2 and the 30-boronate 3 via a Suzuki coupling
reaction (Scheme 1).
Keywords: gem-Difluoromethylenated compound;Biflavonoid;Suzuki
reaction.
*
Corresponding author. Tel.: +86 21 64163300;fax: +86 21
64166128;e-mail: flq@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.180

8084
X. Zheng et al. / Tetrahedron Letters 45(2004) 8083–8085
OH
OH
HO
OH
CHO
92%
/ NaOH
a) HO
b) HCl
HO
O
O
a) ClCH2CN / ZnCl2 / HCl
b) H2O
65%
Cl
HO
OH
OH
O
OH
6
7
46%
HCF Cl / NaOH
2
OCF2H
OCF2H
OCF2H
HCF2O
O
HCF2O
O
HCF2O
O
AgOAc / I2
88%
CH3I / K2CO3
93%
I
I
OH
O
OMe
O
OH
O
5
2
4
Scheme 2.
I
OMe
I
MeO
CHO
10
HO
OH
O
HO
O
HO
OH
90%
Cl
9
O
11
CH3I / K2CO3
95%
O
O
B
OMe
OMe
2
MeO
O
Bis(pinacolato)diboron
PdCl2(dppf)
I
MeO
O
1
Pd(PPh3)4
33%
3
8
O
O
Scheme 3.
in dioxane/H2O and compound 5 was obtained in 46%
yield.8 The iodination of 5,7-dioxygenated flavones are
known to occur rather at C8.4,9 To our best knowledge,
there were two methodologies, to provide 6-iodoflav-
ones in good yield in the literature. One of them
required TlOAc, a highly toxic reagent,10 the other
was regioselective 6-iodination of 5,7-dioxygenated flav-
ones by the use of benzyltrimethylammonium dichloro-
iodate.9 We regioselectively prepared 6-iodonated
flavone 4 in 88% yield from compound 5 with AgOAc/
I2 under mild conditions.11 The methylation of 4 was
accomplished with CH3I in the presence of K2CO3 to
give compound 2 in 93% yield.
gave the desired biflavonoid 113 in 33% yield based on
compound 8.
In summary, we have described
a synthesis of
gem-difluoromethylenated biflavonoid 1 via the Suzuki
coupling reaction. The key intermediate 6-iodonated
flavone 4 was regioselectively synthesized by the use of
AgOAc/I2 under mild conditions without the handling
of a strongly toxic reagent.
Acknowledgements
We thank the National Natural Science Foundation of
China, Ministry of Education of China and Shanghai
Municipal Scientific Committee for funding this work.
Compound 3 was prepared according to Scheme 3.
Compound 11 was prepared from resorcinol in the same
manner as compound 7. Compound 10, prepared from
4-methoxybenzaldehyde with ICl in AcOH at 60°C,
was reacted with 11 in the presence of excess NaOH in
H2O/EtOH and followed by acidification with aqueous
HCl to give the expected compound 9 in 90% yield.
The methylation of 9 was carried out with CH3I in the
presence of K2CO3 in acetone to afford 8 in 95% yield.
Following the literature procedure,10 a mixture of com-
pound 8, bis(pinacolato)diboron, KOAc and PdCl2
(dppf) in DMF was stirred at 80°C overnight. The
expected compound 3 was obtained by column chroma-
tography on silica gel. The cross coupling of compound
3 with 2 by a standard Suzuki reaction conditions12
References and notes
1. Flavonoids in Health and Disease;Rice-Evans, C. A.,
Packer, L., Eds.;Marcel Dekker: New York, 1997.
2. Lin, Y. M.;Anderson, H.;Flavin, M. P.;Pai, Y. H. S.;
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1997, 60, 884–888.
3. Vlietinck, A. J.;Bruyne, T.;De Apers, S.;Pieters, L. A.
Planta Med. 1998, 64, 97–109.
4. Zheng, X.;Meng, W. D.;Xu, Y. Y.;Cao, J. G.;Qing, F.
L. Bioorg. Med. Chem. Lett. 2003, 13, 881–884.

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6. Chen, J. J.;Yang, W. W.;Pan, X. F.;Tan, Z. Acta Chim.
Sinica 1987, 45, 503–505.
7. Al-Maharik, N.;Botting, N. P. Tetrahedron 2003, 59,
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s), 3.97 (3H, s), 4.00 (3H, s), 6.86 (1H, s), 6.92 (1H, dd,
J = 2.0, 8.8Hz), 7.06 (1H, s), 7.17 (1H, d, J = 8.8Hz), 7.22
(1H, d, J = 2.0Hz), 7.39 (1H, t, J = 72.4Hz), 7.43 (2H, d,
J = 8.8Hz), 7.48 (1H, t, J = 73.2Hz), 7.61 (1H, s), 7.74
(1H, d, J = 8.8Hz), 8.05 (1H, dd, J = 2.0, 8.8Hz), 8.24
(2H, d, J = 8.8Hz), 8.46 (1H, d, J = 2.0Hz); 19F NMR
8. Bernard, R. L. J. Fluorine Chem. 1988, 41, 247–
261.
(376MHz):
d
J = 72.4Hz). Anal. Calcd for C35H24F4O9: C, 63.26;H,
ꢀ83.09 (d, J = 73.2Hz), ꢀ83.78 (d,
9. Quintin, J.;Lewin, G. Tetrahedron Lett. 2004, 45, 3635–
3638.
10. Zembower, D. E.;Zhang, H. J. Org. Chem. 1998, 63,
9300–9305.
3.64. Found: C, 63.11;H, 4.08. Compound 2 mp 230–
1
232°C. H NMR (400MHz, CDCl3): d 3.97 (3H, s), 6.00
(1H, t, J = 72.8Hz), 6.68 (1H, t, J = 72.0Hz), 6.69 (1H, s),
7.17 (2H, d, J = 8.8Hz), 7.18 (1H, s), 7.88 (2H, d,
11. The experimental procedure for the conversion of 5 to 4:
To a solution of 5 (310mg, 0.8mmol) in CH2Cl2 (30mL)
was added silver acetate (158mg, 0.9mmol). Then a
solution of iodine (230mg, 0.9mmol) in CH2Cl2 (40mL)
was added dropwise over 1h. After stirring the resulting
mixture at room temperature for 36h, the reaction mixture
was filtered and the precipitated silver iodide was washed
with CH2Cl2. The combined filtrates were washed with a
10% aqueous solution of Na2SO3, brine and dried over
anhydrous MgSO4. After removal of the solvent, the
residue was purified by flash chromatography on silica gel
(petroleum ether–CH2Cl2 = 1:1) to give 4.
J = 8.8Hz). 19F NMR (376MHz):
d
ꢀ82.36 (d,
J = 72.8Hz), ꢀ81.70 (d, J = 72.0Hz);HRMS Calcd for
C18H11IF4O5: 509.9587;Found: 509.9545. Compound
4
1
mp 236–238°C. H NMR (300MHz, CDCl3): d 6.64 (1H,
t, J = 73.2Hz), 6.69 (1H, t, J = 72.3Hz), 6.77 (1H, s), 6.93
(1H, s), 7.30 (2H, d, J = 9.0Hz), 7.94 (2H, d, J = 9.0Hz),
13.82 (1H, s). 19F NMR (282MHz): d ꢀ82.33 (d,
J = 73.2Hz), ꢀ81.99 (d, J = 72.3Hz);HRMS Calcd for
C17H9IO5F4: 495.9411;Found: 495.9411. Compound
5
1
mp 151–152°C. H NMR (300MHz, CDCl3): d 6.57 (1H,
d, J = 2.1Hz), 6.63 (1H, t, J = 72.6Hz), 6.64 (1H, t,
J = 72.9Hz), 6.69 (1H, s), 6.75 (1H, d, J = 2.1Hz), 7.29
(2H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz). 19F NMR
12. Dansou, B.;Pichon, C.;Dhal, R.;Brown, E.;Mille, S.
Eur. J. Org. Chem. 2000, 8, 1527–1534.
13. Physical data for some new compounds. Compound 1 mp
(282MHz):
J = 72.6Hz);Anal. Calcd for C 17H10F4O5: C, 55.15;H,
d
ꢀ82.59 (d, J = 72.9Hz), ꢀ82.08 (d,
1
177–179°C. H NMR (400MHz, DMSO-d6): d 3.87 (3H,
2.72. Found: C, 55.12;H, 2.80.