Site-Selective Suzuki-Miyaura Reaction of 6,8-Dibromoflavone

Article abstract of DOI:10.1055/s-0035-1560633

8-Aryl- and 6,8-diarylflavones were prepared by Suzuki-Miyaura reactions of 6,8-dibromoflavone. In spite of the greater steric hindrance, the first attack proceeded with good site selectivity at position 8.

Full text of DOI:10.1055/s-0035-1560633

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 26, 2601–2605
2601
letter
Synlett
D. Pajtás et al.
Letter
Site-Selective Suzuki–Miyaura Reaction of 6,8-Dibromoflavone
Dávid Pajtása
Károly Dihena
O
Ar1
Tamás Patonaya
Krisztina Kónyaa
Alexander Villingerb
Peter Langer*b,c
O
Ph
1
Ar B(OH)2
Ar1
O
O
Br
86–99% yield
examples
Pd(PPh3)4
K3PO4
7
a
Department of Organic Chemistry, University of Debrecen,
dry 1,4-dioxane
Ph
O
Egyetem tér 1, 4032 Debrecen, Hungary
Department of Chemistry, Organic Chemistry, University of Rostock,
b
Ar2
Br
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Leibniz-Institute for Catalysis e.V. at the University of Rostock (LIKAT),
1
1) Ar B(OH)2
c
2
2) Ar B(OH)2
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
O
Ph
Ar1
1–94% yield
examples
8
4
1
Received: 14.07.2015
Accepted after revision: 18.09.2015
Published online: 18.09.2015
by Handy and Zhang based on H NMR spectroscopic chem-
10c
ical shift values. The Suzuki–Miyaura coupling has been
recently employed to modify the flavone core structure.
11
DOI: 10.1055/s-0035-1560633; Art ID: st-2015-d0544-l
Herein, we wish to report what are, to the best of our
knowledge, the first site-selective Suzuki–Miyaura reac-
tions of 6,8-dibromoflavone. These reactions provide a con-
venient approach to a variety of novel arylated flavone de-
rivatives.
Abstract 8-Aryl- and 6,8-diarylflavones were prepared by Suzuki–
Miyaura reactions of 6,8-dibromoflavone. In spite of the greater steric
hindrance, the first attack proceeded with good site selectivity at posi-
tion 8.
Key words palladium, catalysis, flavones, Suzuki–Miyaura reaction, re-
gioselectivity
Bromination of commercially available 2′-hydroxyaceto-
phenone (1) gave 3′,5′-dibromo-2′-hydroxyacetophenone
(
2) in good yield.12 Product 2 was converted into dibromo-
13
Flavones (2-aryl-4H-1-benzopyran-4-ones) are wide-
chalcone 3 by Claisen–Schmidt condensation. The ring-
closure of 3, carried out in the presence of a catalytic
amount of iodine in hot dimethyl sulfoxide,14 resulted in
the corresponding dibromoflavone 4 (Scheme 1).
1
spread in nature as plant metabolites. Versatile biological
activities of flavone derivatives were observed, for example,
antioxidant, antimicrobial, antiproliferative, anti-inflam-
matory, and central nervous system protective properties.1
Most syntheses of flavones are based on the corresponding
chromone (4H-1-benzopyran-4-one) core structure by con-
–4
OH
O
O
Br
i
2,3
ventional methods. Arylated flavone derivatives show dif-
ferent biological activities, for example, cytotoxic, antibac-
terial, antiviral, anti-inflammatory, enzyme inhibition, and
even DNA repairing properties have been displayed.5
The Suzuki–Miyaura reaction, a palladium-catalyzed C–C
coupling of boronic acids with aryl halides, triflates, or
OH
Br
1
2
(66%)
ii
6
tosylates, was first published in 1979. The advantages of
the Suzuki coupling include the commercial availability of
arylboronic acids, the mild reaction conditions, as well as
O
O
O
Br
Br
7
iii
Ph
the high functional group tolerance. Several ligands and
8
catalysts have been reported. Due to the difference be-
OH
Ph
tween their reactivity, the chemoselectivity depends on the
type of the leaving groups (ArI > ArBr > ArOTf > ArCl >
ArOTs). In the case of dihalogenated substrates containing
Br
Br
4
(80%)
3 (68%)
9
Scheme 1 Synthesis of 4. Reagents and conditions: (i) 1 (1.0 equiv), Br2
2.2 equiv), AlCl (1.5 equiv), DCE, 84 °C, 2 h; (ii) PhCHO (1.5 equiv),
3
only one type of leaving group, the regioselectivity is con-
(
10
trolled by electronic and steric factors. The regioselectivi-
ty of palladium(0)-catalyzed cross-coupling reactions of
substances can be predicted with a simple guide suggested
KOH (4.0 equiv), EtOH–H O, 20 °C, overnight; (iii) I (cat.), DMSO,
2
2
180 °C, 15 min.
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D. Pajtás et al.
Letter
The Suzuki–Miyaura reaction of 4 with arylboronic
acids 5a–g (3.0 equiv) afforded 6,8-diarylflavones 6a–g in
first coupling to the more electron-deficient C8 site. How-
ever, we observed that, besides the desired products 7a–d,
unreacted 6,8-dibromoflavone (4), the corresponding dia-
rylated, and the isomeric monocoupled byproducts 8a–d
were also present in small amounts in the crude reaction
mixture (vide infra). Products 7a–d were isolated in pure
form by chromatography. The best yields were obtained us-
ing only 1.2 equivalents boronic acid with Pd(PPh3)4 (6
mol%) in dry 1,4-dioxane at a temperature of 80 °C.
15
very good yields (Scheme 2, Table 1). Both electron-poor
and electron-rich arylboronic acids were successfully em-
ployed. However, boronic acids with an electron-donating
group reacted more rapidly; others with electron-with-
drawing substituents needed more time and higher tem-
peratures to achieve a full conversion. The reactions were
carried out in abs.1,4-dioxane at 90–100 °C using Pd(PPh3)4
(
6 mol%) as catalyst and K PO (3.0 equiv) as base. Monitor-
3 4
ing of the reaction by TLC revealed that the monoarylated
product was initially formed. Before all the starting materi-
al 4 was consumed, the diarylated product started to be
formed until full conversion of 4.
O
Br
O
Ph
O
O
ArB(OH)2
Ar
Br
5a–c,g
O
7a–d
+
O
Br
ArB(OH)2
Ar
i
O
Ph
5a–g
Br
Ar
O
Ph
i
4
O
Ph
Br
Ar
O
Ph
4
6a–g
Br
Scheme 2 Synthesis of 6a–g. Reagents and conditions: (i) 4 (1.0 equiv),
8a–d
5
a–g (3.0 equiv), Pd(PPh ) (6 mol%), K PO (3.0 equiv), dry 1,4-diox-
3 4 3 4
Scheme 3 Synthesis of 7a–d. Reagents and conditions: (i) 4 (1.0 equiv),
ane, 90–100 °C.
5
a–c,g (1.2 equiv), Pd(PPh ) (6 mol%), K PO (2.0 equiv), dry 1,4-diox-
3
4
3
4
ane, 80 °C, 48 h.
Table 1 Synthesis of 6a–g
Table 2 Synthesis of 7a–d
Entry
5
6
Ar
Temp
°C)
Time
(h)
Yields 6
(
(%)a
Entry
5
7
Ar
Yield of 7a
and 8 (%)
1
2
3
4
5
6
5a
5b
5c
5d
5d
5f
6a
6b
6c
6d
6e
6f
4-MeC
6
H
4
90
2
5
93
86
99
96
83
95
94
1
2
3
5a
5b
5c
5g
7a
7b
7c
7d
4-MeC
4-MeOC
3,4-(MeO)
4-F CC
6
H
4
47
59
57b
57
4-MeOC
6
H
4
90
100
100
100
100
100
6
H
4
3,4-(MeO)
2
C
6
H
3
15
15
24
24
24
2 6 3
C H
Ph
4
3
6
H
4
4-ClC
4-FC
4-F CC
6 4
H
a
Yields refer to pure isolated products.
Product 8c was isolated in pure form (12% yield).
6
H
4
b
7
5f
6g
3
6 4
H
a
Yields refer to pure isolated products.
All products were characterized by spectroscopic meth-
ods (NMR, IR, MS, HRMS). The structural characterization of
products 7a–d was supported by 2D NMR experiments
(HMBC, NOESY). In the case of 7c, besides the pure isolated
product 7c, a fraction containing a 4.7:1 mixture of 7c along
with its isomeric byproduct 8c was isolated. This allowed
the unequivocal identification of 8c by NOESY measure-
ments (Figure 1). The structure of 7c was independently
6
,8-Dibromoflavone (4) was also successfully trans-
formed into 6-bromo-8-arylflavones 7a–d by a Suzuki–Mi-
yaura reaction using arylboronic acids 5a–c,g. The reactions
were performed in moderate to good yields and with very
16a
good site selectivity (Scheme 3, Table 2). Both electron-
poor and electron-rich arylboronic acids were successfully
used. According to Handy and Zhang’s method, which use
17
confirmed by X-ray crystal-structure analysis (Figure 2).
1
the H NMR chemical shifts of the nonhalogenated parent
The Suzuki–Miyaura reaction of monoarylated deriva-
compounds in case of polyhalogenated heteroaromatics,
the predicted regioselectivity of 6,8-dibromoflavone (4) is
C8 > C6. In this case, the electronic difference is quite small
as showed by a modest (Δδ = 0.15) chemical shift differ-
ence between C6 and C8, but still sufficient to direct the
tives 7c and 7d with arylboronic acids 5a and 5e (2.0 equiv)
provided 6,8-diarylflavones 9a–d (Scheme 4, Table 3).
The reactions were carried out at 100 °C and resulted in
high yields. No marked electronic effects of the substituents
on the yield were observed.
18,19
16b
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D. Pajtás et al.
Letter
Table 3 Synthesis of 9a–d
Entry
7
5
9
R1
R2
Yieldsof
9
(%)a
1
2
3
7c
7c
7d
7d
5a
5e
5a
5e
9a
9b
9c
9d
3,4-(MeO)
2
C
C
6
H
3
3
4-MeC
4-ClC
4-MeC
4-ClC
6
H
4
93
81
89
94
3,4-(MeO)
2
6
H
6
H
4
4-F
3
3
CC
CC
6
H
H
4
4
6
H
4
4
4-F
6
6 4
H
a
Yields refer to pure isolated products
In conclusion, we have reported the synthesis of a vari-
ety of arylated flavones by site-selective Suzuki–Miyaura
reactions of 6,8-dibromoflavone. Various boronic acids
were reacted smoothly under mild conditions, providing
different mono-/bis-/diarylated derivatives of flavone in
good to excellent yields. The regioselectivity of 6,8-dibro-
moflavone was predicted by Handy and Zhang’s method,
however, the method was developed based on the reactions
Figure 1 NOESY measurements of 7c and 8c
1
of polyhalogenated heteroaromatics and H NMR chemical
shifts of their the nonhalogenated parent compounds. The
first attack occurred at the more electron-deficient center
C8, providing 8-monoarylflavones in good yields. The sec-
ond bromide (C6) also could take part in the coupling reac-
tion, although it requires more vigorous conditions as our
experiments showed. In case of the synthesis of symmetri-
cally arylated compounds the cross-coupling took place for
longer time using electron-poor boronic acids. However, the
reaction of 8-monoarylflavones with different boronic ac-
ids did not show electronic effects of the substituents of the
boronic acid.
Acknowledgement
Financial support by the Alexander-von-Humboldt Foundation (Insti-
tute partnership program) and by the State of Mecklenburg-Vorpom-
mern (scholarships for D.P. and K.D.) is gratefully acknowledged.
Supporting Information
Figure 2 Crystal structure of 7c17
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560633.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
O
O
Br
Ar2
ArB(OH)2
5
a,e
i
References and Notes
O
Ph
O
Ph
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7
c,d
9a–d
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1
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(15) Procedure for Synthesising 6,8-Diarylflavone Derivatives 6a–g
To a mixture of 6,8-dibromoflavone (4, 95 mg, 0.25 mmol),
K PO (160 mg, 0.75 mmol), and boronic acid 5 (0.75 mmol) in
(
3
4
2
dry dioxane (4 mL), Pd(PPh ) (17 mg, 0.015 mmol) was added
3 4
Organometallics in Process Chemistry; Larsen, R. D., Ed.;
Springer: Berlin, 2004. (h) Suzuki, A. Modern Arene Chemistry;
Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002. (i) Miyaura, N. Top.
Curr. Chem. 2002, 219, 11. (j) Suzuki, A. J. Organomet. Chem.
in a dried pressure tube under argon. The reaction mixture was
stirred and heated in an aluminum heating block till full conver-
sion. The solvent was removed under reduced pressure, and the
solid mixture was dissolved in CH Cl . The solution was submit-
2
2
2002, 653, 54. (k) Roglans, A.; Pla-Quintana, A.; Moreno-Mañas,
ted to adsorptive filtration on silica gel using CH Cl as eluent to
2 2
M. Chem. Rev. 2006, 106, 4622. (l) Hassan, J.; Sévignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
remove the inorganic compounds. The CH Cl was evaporated;
2 2
the residue was washed two times with acetone then filtered to
give the pure cross-coupled product 6.
(m) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133. (n) Wu, X. F.;
Anberasan, P.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed.
(16) (a) Procedure for Synthesising 8-Aryl-6-bromoflavone Deriv-
atives 7a–d
2010, 49, 9047. (o) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006,
106, 2651.
To a mixture of 6,8-dibromoflavone (4, 95 mg, 0.25 mmol),
K PO (106 mg, 0.5 mmol), and boronic acid 5 (0.30 mmol) in
3
4
dry dioxane (4 mL), Pd(PPh ) (17 mg, 0.015 mmol) was added
3
4
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D. Pajtás et al.
Letter
in a dried pressure tube under argon. The reaction mixture was
stirred and heated at 80 °C for 48 h in an aluminum heating
block. The solvent was removed in vacuum, and the solid
mixture was dissolved in CH Cl . The solution was submitted to
122.1 (C-5), 126.9 (C-3), 21.3 (4′′′-CH ), 21.1 (4′′-CH ). IR (ATR):
3
3
ν = 1636, 1597, 1459, 1447, 1363, 1173, 812, 775, 687, 633, 502
–1
+•
cm . GC-MS (EI, 70eV): m/z (%) = 402 (100) [M ], 300, 229, 102.
HRMS: m/z calcd for C29H22O : 402.16143; found: 402.16156.
2
2
2
adsorptive filtration on silica gel using CH Cl as eluent to
6-Bromo-8-(3,4-dimethoxyphenyl)flavone (7c)
2
2
remove the inorganic compounds. The eluted solution was con-
centrated then the mixture was purified by column chromatog-
raphy (eluent: heptane–EtOAc mixture; the ratio is given at the
Starting with 4 (95 mg, 0.25 mmol), K PO (106 mg, 0.5 mmol),
3
4
Pd(PPh3)4 (17 mg, 0.015 mmol, 6 mol%), (3,4-dimethylphe-
nyl)boronic acid (5c, 55 mg, 0.30 mmol), and 1,4-dioxane (4
mL), 7c was isolated as a white solid (62 mg 57%), mp 186.5–
compound) to give the monosubstituted product.
1
1
(
b) H NMR Spectroscopic Data of Flavone
188 °C (eluent: heptane–EtOAc, 2:1). H NMR (300 MHz, 298 K,
1
H NMR (400 MHz, CDCl ): δ = 8.24 (d, J = 8.9 Hz, 1 H, 5-H),
CDCl ): δ = 8.31 (d, 1 H, J = 2.4 Hz, 5-H), 7.80 (d, 1 H, J = 2.4 Hz,
3
3
7
.97–7.89 (m, 2 H, 2′,6′-H), 7.70 (t, J = 8.4 Hz, 1 H, 7-H), 7.58 (d,
7-H), 7.77–7.75 (m, 2 H, 2′,6′-H), 7.51–7.45 (m, 3 H, 3′,5′-H, 4′-
H), 7.18–7.15 (m, 2 H, 2′′,6′′-H), 7.04 (d, J = 8.1 Hz, 1 H, 5′′-H),
6.88 (s, 1 H, 3-H), 3.99 (s, 3 H, 4′′-OCH ), 3.88 (s, 3 H, 3′′-OCH ).
J = 8.3 Hz, 1 H, 8-H), 7.56–7.50 (m, 3 H, 3′,4′, 5′-H), 7.43 (t, J = 7.5
Hz, 1 H, 6-H), 6.83 (s, 1 H, 3-H).
3
3
13
(
17) CCDC-1052200 contains all crystallographic details of this pub-
C NMR (75 MHz, 298 K, CDCl ): δ = 177.1 (C-4), 163.3 (C-2),
3
lication
and
is
available
free
of
charge
at
151.9 (C-8a), 149.4 (C-3′′), 148.7 (C-4′′), 137.0 (C-7), 133.8 (C-
1′′), 131.8 (C-4′), 131.2 (C-1′), 129.0 (C-3′,5′), 127.3 (C-8), 126.9
(C-5), 126.2 (C-2′,6′), 125.6 (C-4a), 122.2 (C-6′′), 118.6 (C-6),
112.6 (C-2′′), 111.1 (C-5′′), 106.9 (C-3), 55.9 (3′′-OCH , 4′′-OCH ).
www.ccdc.cam.ac.uk/conts/retrieving.html.
(
18) Procedure for Synthesizing Differently Substituted 6,8-Dia-
rylflavone Derivatives 9a–d
3
3
To a mixture of 8-aryl-6-bromoflavones 7c,d (0.10 mmol),
K PO (54 mg, 0.25 mmol), and boronic acid 5a,e (0.20 mmol) in
IR: (ATR): ν = 3061, 2999, 2933, 2838, 1637, 1567, 1512, 1452,
–1
1358, 1251, 1224, 1137, 1022, 882, 780, 694, 670, 637, 589 cm
.
3
4
+
•
+•
dry dioxane (4 mL), Pd(PPh ) (5.8 mg, 0.005 mmol) was added
GC-MS (EI, 70eV): m/z (%) = 436 [M ], 438 [M + 2], 293, 291,
3
4
in a dried pressure tube under argon. The reaction mixture was
stirred and heated at 100 °C for 2 h in an aluminum heating
block. The solvent from the crude reaction mixture was
removed in vacuum, and the solid residue was dissolved in
CH Cl . The solution was submitted to adsorptive filtration on
184, 102. HRMS: m/z calcd for C23H17O
479Br: 436.03047; found:
436.03046; m/z calcd for C23H17O481Br: 438.02843; found:
438.02866.
6-(4-Chlorophenyl)-8-(3,4-dimethoxyphenyl)flavone (9b)
Starting with 7c (44 mg, 0.10 mmol), K PO (42 mg, 0.2 mmol),
2
2
3
4
silica gel using CH Cl as eluent to remove the inorganic com-
Pd(PPh3)4 (5.8 mg, 0.005 mmol,
5
mol%), (4-chlorophe-
2
2
pounds. The eluted solution was concentrated, then the mixture
was purified by column chromatography (eluent: heptane–
EtOAc mixture; the ratio is given at the compound) to give the
nonsymmetric diarylated product.
nyl)boronic acid (5e, 31 mg, 0.20 mmol), and 1,4-dioxane (4
mL), 9b was isolated as a light yellow solid (38 mg, 81%), mp
228–229 °C (eluent: heptane–EtOAc, 2:1). H NMR (300 MHz,
1
298 K, CDCl ): δ = 8.40 (d, J = 3.0 Hz, 1 H, 5-H), 7.90 (d, J = 3.0 Hz,
3
(
19) 6,8-Bis(4-methylphenyl)flavone (6a)
1 H, 7-H) 7.82–7.90 (m, 2 H, 2′,6′-H), 7.64 (d, J = 8.1 Hz, 2 H,
2′′,6′′-H,) 7.52–7.43 (m, 5 H, 3′,5′-H, 4′-H, 3′′,5′′-H), 7.25–7.21
(m, 2 H, 2′′′,6′′′-H), 7.07 (d, J = 8.1 Hz, 1 H, 5′′′-H), 6.93 (s, 1 H, 3-
Starting with 4 (95 mg, 0.25 mmol), K PO (160 mg, 0.75 mmol),
3
4
Pd(PPh3)4 (17 mg, 0.015 mmol,
6
mol%), (4-methylphe-
13
nyl)boronic acid (5a, 102 mg, 0.75 mmol), and 1,4-dioxane (4
mL), 6a was isolated as a light yellow solid (94 mg 93%), mp
H), 4.00 (s, 3 H, 4′′′-OCH ), 3.90 (s, 3 H, 3′′-OCH ). C NMR (75
3
3
MHz, 298 K, CDCl ): δ = 178.4 (C-4), 163.2 (C-2), 152.6 (C-8a),
3
2
47.0–248.5 °C. 1H NMR (300 MHz, 298 K, CDCl ): δ = 8.44 (d,
149.3 (C-3′′′), 148.8 (C-4′′′), 137.7 (C-1′′), 136.9 (C-6), 134.1 (C-
4′′), 133.1 (C-7), 132.4 (C-1′′′), 131.8 (C-4′), 131.5 (C-1′), 129.2
(C-3′,5′), 129.1 (C-3′′,5′′), 128.6 (C-8), 128.4 (C-2′′,6′′), 126.3 (C-
2′,6′), 124.7 (C-4a), 122.3 (C-5), 122.2 (C-6′′′), 112.9 (C-2′′′),
111.2 (C.5′′′), 106.9 (C-3), 56.0 (3′′′-OCH , 4′′′-OCH ). IR (ATR):
3
J = 2.7 Hz, 1 H, 5-H), 7.96 (d, J = 2.4 Hz, 1 H, 7-H), 7.82–7.79 (m,
2
3
H, 2′,6′-H), 7.64–7.59 (m, 4 H, 2′′,6′′-H, 2′′′,6′′′-H), 7.49.7.46 (m,
H, 3′,5′-H, 4′-H), 7.37 (d, J = 9.6 Hz, 2 H, 3′′′,5′′′-H), 7.27 (d,
J = 9.6 Hz, 2 H, 3′′,5′′-H), 6.96 (s, 1 H, 3-H), 2.50 (s, 3 H, 4′′′-CH ),
3
3
3
13
2
.42 (s, 3 H, 4′′-CH3). C NMR (75 MHz, 298 K, CDCl ): δ = 178.7
ν = 2957, 2834, 1640, 1514, 1461, 1243, 1225, 1141, 1029, 821,
3
–1
+•
+•
(C-4), 163.2 (C-2), 152.4 (C-8a), 138.1 (C-4′′,4′′′), 137.8 (C-6),
688 cm . GC-MS (EI, 70eV): m/z (%) = 468 [M ], 470 [M + 2],
425, 323, 189, 102. HRMS: m/z calcd for C29H21O435Cl:
468.11229; found: 468.11195.
136.4 (C-8), 133.4 (C-7), 133.2 (C-1′′), 132.3 (C-1′′′), 131.6 (C-1′),
131.5 (C-4′), 129.7 (C-3′′,5′′), 129.5 (C-3′′′,5′′′), 129.1 (C-2′′′,6′′′),
129.0 (C-3′,5′), 127.0 (C-2′′,6′′), 126.3 (C-2′,6′), 124.5 (C-4a),
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2601–2605