Selective O-demethylation during bromination of (3,4-dimethoxyphenyl)(2,3, 4-trimethoxyphenyl)methanone

Article abstract of DOI:10.1016/j.tet.2011.03.033

(3,4-Dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methanone was synthesized and its bromination was investigated in different conditions. Nine new products (bromophenol derivatives) were isolated in the reactions. These bromophenol derivatives were obtained by selective O-demethylation in its bromination with bromine. The products and their formations were discussed.

Full text of DOI:10.1016/j.tet.2011.03.033

Tetrahedron 67 (2011) 3483e3489
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Selective O-demethylation during bromination of (3,4-dimethoxyphenyl)
(2,3,4-trimethoxyphenyl)methanone
,
a
a,b
Yasin C¸ etinkaya a, Abdullah Menzek a , Ertan S¸ ahin , Halis Turker Balaydın
*
€
a
€
Department of Chemistry, Faculty of Science, Ataturk University, 25240 Erzurum, Turkey
b Education Faculty, Artvin C¸ oruh University, 08000 Artvin, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
(3,4-Dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methanone was synthesized and its bromination was
investigated in different conditions. Nine new products (bromophenol derivatives) were isolated in the
reactions. These bromophenol derivatives were obtained by selective O-demethylation in its bromination
with bromine. The products and their formations were discussed.
Received 4 December 2010
Received in revised form 23 February 2011
Accepted 14 March 2011
Available online 21 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bromophenol
Bromination
Selective O-demethylation
Br
Br
Br
Br
Br
1. Introduction
OH
OH
Br
Br
Br
Organohalogens, especially organobromides, serve as starting
materials for many target molecules. Organobromides,1 such as
bromophenols are important compounds. For example, bromo-
phenol 1 exhibits enzyme inhibition,2 cytotoxicity,3 feeding de-
terrent,4 and microbial5 activities. Antioxidant activities6 of
bromophenols 1, 3, and 4 and significant aldose reductase inhibitory
activity7 of bromophenols 2 and 3 were also noted (Scheme 1).
Brominated derivatives of compound 4 also have important
antioxidant activities.6a Compound 5, in similar to 4, and its bro-
minated derivatives are potential biologically active compounds.
For the synthesis of compound 5 and its derivatives with Br, com-
pound 6 should be synthesized and then its bromination and
demthylation reactions should be realized because phenolic OH
groups are usually protected as arylmethylethers in synthesis.6a,8
Furthermore, interesting products including Br, OH, and OMe
groups may be observed. Therefore, the synthesis of compound 6
and its brominations were investigated.
HO
OH
HO
R
Br
OH
OH
OH
1
2
3
R = H
R = Br
OR
O
O
OR
OR
RO
HO
OH
OR
OH
OH
5
6
R = H
R = Me
4
Scheme 1.
2. Result and discussion
Brominations of compound 6 under different conditions were
investigated for the synthesis of its new brominated derivatives.
Selectively, aromatic compounds with ceric ammonium nitrate
(CAN)/LiBr react to give brominated product(s).9 Bromination of 6
with 1.1 and 2.2 equiv of LiBr/CAN at rt gave a monobromide and
a mixture of mono- and dibromides, respectively (Scheme 3, Table 1).
An AB-system in the 1H NMR spectrum of monobromide is
similar to that of aromatic ring with two OMe of 6. Electrophilic
(3,4-Dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methanone
(6) was obtained from the reaction of 3,4-dimethoxybenzoic acid
(7) and 1,2,3-trimethoxybenzene (8) in polyphosphoric acid (PPA)
by the literature method (Scheme 2).6a,8c,d
* Corresponding author. E-mail address: amenzek@atauni.edu.tr (A. Menzek).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.033

3484
Y. C¸ etinkaya et al. / Tetrahedron 67 (2011) 3483e3489
OMe
O
OMe
OMe
COOH
OMe
OMe
PPA, 80 °C
+
OMe
93%
MeO
MeO
OMe
OMe
8
6
7
Scheme 2.
OMe
O
OMe
Br
OMe
O
O
CAN/LiBr
(2.2equiv)
OMe
OMe
OMe
OMe
+
CH3CN
MeO
OMe
MeO
OMe
MeO
OMe
OMe
Br
OMe
Br
6
9
10
70%
23%
Scheme 3.
substitution of bromine should be in the meta position with respect
to CO group in the ring with three OMe of 6 because of the electron
density of this ring and the orientations of CO and OMe groups.
Monobromide should be structure 9. Chromatography on silica gel
of the mixture obtained from bromination of 6 with 2.2 equiv of
LiBr/CAN permitted the isolation of monobromide 9 and a dibro-
mide. The structure of dibromide should be 10 because three peaks
were present as singlet(s) while no AB-system was present in the
aromatic region of its 1H NMR spectrum. Dibromide 10 should be
formed of a reaction of bromine with monobromide 9.
Table 1
Bromination reactions of the compound 6 (1.0 equiv) at different conditions and
yields % of the product(s)
R (E)
T (Time)
% Yields of the product (s)
9
10 11 12 13 14 15 16 18
LiBr (1.1)/CAN (1.1)a
LiBr (2.2)/CAN (2.2)a,d
LiBr (6.0)/CAN (6.0)a
Br2 (1.1)b
rt (1 d)
rt (15 d)
rt (6 d)
rt (1 d)
rt (2.5 d)
rt (8 d)
97
d
d
96
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
5
d
d
d
d
d
d
d
d
d
d
d
25 75
95
d
d
d
Br2 (2.2)b,d
88 12
d
Br2 (10.0)b
2
1.4 73 13 2.4
20 1.9 68 1.6
1.5 74 11 2.1
Bromination of 6 with 6.0 equiv of LiBr/CAN at rt gave dibromide
10 as the sole product (Table 1). Bromination of 6 with 1.1 and
2.2 equiv of Br2 at rt gave monobromide and a mixture of mono-
and dibromides, respectively (Table 1).
Br2 (6.0)b
Ref. (3 d)
Ref. (8 d)
6
d
d
Br2 (10.0)b
3
d
Fe (powder)/Br2 (10.0)c Ref. (5 h)
Fe (powder)/Br2 (10.0)d Ref. (1.5 h)
d
d
d
d
19 63
33 59
d
d
d
d
d
8
A solution in CHCl3 of 6 with Br2 (6.0 equiv) at reflux temperature
was reacted to give five products (Scheme 4, Table 1). According to
NMR, they are two dibromides and three bromophenols. One of the
dibromides is 10 and the other dibromide has an AB-system whose
peaks at 7.20 ppm as dd (J¼1.9, 8.4 Hz) and at 6.84 ppm as
d(J¼8.4 Hz) aresimilar tothoseof the aromatic ringwithtwoOMe of
6. Therefore, this dibromide should be structure 11.
(R¼Reagent(s), E¼equivalent, CAN¼Ceric ammonium nitrate, T¼Temperature,
rt¼Room temperature, d¼Day, h¼Hour, Ref.¼Reflux).
a
(CH3CN)
b
(CHCl3)
c
(HOAc) are the solvent of the reactions.
d
Percent of products in the mixture (according to 1H NMR)
OMe
O
Br
OMe
O
OMe
O
OMe
OMe
OMe
OMe
OMe
OMe
Br2 (6 equiv.)
+
CHCl3
Reflux
MeO
MeO
MeO
Br
OMe
OMe
Br
OMe
Br
Br
6
10
11
1.9%
20%
Br
OH
OH
Br
OH
O
O
O
Br
OMe
OMe
OMe
OMe
OMe
OMe
+
+
+
MeO
MeO
Br
MeO
OMe
Br
OMe
Br
OMe
Br
13
14
12
68%
1.6%
6%
Scheme 4.

Y. C¸ etinkaya et al. / Tetrahedron 67 (2011) 3483e3489
3485
It was seen that OCH3 groups were demethylated into OH
groups in the reaction condition because the 1H NMR spectra of
bromophenols include one (OH) peak at 12.27e12.06 ppm and
four (OCH3) peaks at 4.09e3.87 ppm as s. One of the bromophe-
nols has three signals (at 7.26, 7.11 and 6.81 ppm) with a 1:1:1
ratio for the aromatic hydrogens. This bromophenol should be
a dibromophenol. Each of the other two bromophenols has two
signals (at 7.17e6.80 ppm) whose ratio is 1:1 for aromatic hy-
drogens. Therefore, each of these bromophenols should be three
bromophenols.
The tribromodimethoxybenzene formed by bond cleavage could
be one of two isomers whose structures are known to be 1,2,3-tri-
bromo-4,5-dimethoxybenzene (18) and 1,2,5-tribromo-3,4-dime-
thoxybenzene because OMe groups are in vicinal position.8c,10 The
NMR data of 1,2,5-tribromo-3,4-dimethoxybenzene has been
reported in literature8c while that of 18 is absent.10a The NMR data of
the formed tribromodimethoxybenzene is not consistent with 1,2,5-
tribromo-3,4-dimethoxybenzene, but its melting point (82e84 ꢀC,
86 ꢀC10a) is consistent with 18. The formation of 18 should have
formed as a result of the reaction of tetrabromide 16 with Brþ via 17.
Bromination reactions of compound 6 under different condi-
tions were given Table 1. The products and their ratios depend on
the reaction conditions. With LiBr/CAN at rt, compounds 9 and 10
were obtained as sole products while products further bromine
were not obtained. Brominated all products were obtained with
molecular Br2 under different conditions. Bromophenols 12e14
should be formed from the corresponding bromides 19. Bromo-
phenols 12e14 were formed during brominations of ketone 6 by
selective O-demethylation.
To our knowledge, selective O-demethylation during bromina-
tion is unknown. As mentioned above, there are five OMe groups in
the compounds such as 10. Two OMe groups of them are one ring
while the others are also other ring. Only, ortho (according to CO)
OMe groups were converted into OH groups from these OMe
groups. There is a similar selective O-demethylation with reagents
such as HCl, HBr, BeCl2 in the literature.11
For selective O-demethylation during the bromination of 6, the
oxygen atom ortho to the CO group and carbon atom of CH3, which is
bound to this oxygen should be less electron-rich. Two reasons may
be mentioned for this. The first is inductive effect of CO group while
the other is the hydrogen bond between oxygen of COand ortho OMe
like 22 and 23 (Scheme 5). The hydrogen bond is favored to the in-
ductive effect of CO group. HBr formed of the electrophilic sub-
stitution of bromine with bromides 19, which convert into 12e14,
was reactedto give intermediate 20. Compound 20 is then converted
into 23 via 22 and then methyl group of ortho OMe in 23 reacts with
Brꢂ to give MeBr and bromophenols 12e14 by SN2 (Scheme 6).
It may mentioned that there is a hydrogen bond between the OH
and CO groups in the bromophenols because they resonate at lower
fields (at 12.27e12.06 ppm for OH and 199.5e197.6 ppm for CO)
than the others, such as 6, 9 and 10 (at 193.0e192.9 ppm for CO).
According to the NMR spectra, the structures of dibromo- and tri-
bromo-phenols may be 12e14, respectively. To make sure that the
positions of the aromatic hydrogen atoms of bromophenols stated
12e14, their exact structures were determined by X-ray diffraction
analysis (Fig. 1). In the structures carbon-bromine distance varies in
ꢀ
the range of 1.886(3)e1.900(4) A. Phenolic rings significantly
twisted with respect to each other depending on the substituted
moeities and their positions. Dihedral angles formed by LSQ-planes
are as follows; 85.8(2)ꢀ, 75.8(2)ꢀ and 84.9(2)ꢀ for compounds
12e14, respectively. Also there are intramolecular hydrogen bonds
in all three structures.
Another method for bromination with Fe/Br2 in acetic acid
(HOAc) was examined. Ketone 6 was heated to reflux with Fe/Br2 in
HOAc at 130ꢁ5 ꢀC for 5 h and three products were isolated in this
bromination reaction by column chromatography (Scheme 5,
Table 1). Based on the NMR spectra of these compounds, it was
determined that they are tribromide, tetrabromide, and tri-
bromodimethoxybenzene. It was not easy to establish the positions
of the aromatic hydrogen atoms in tribromide and tetrabromide.
Therefore, their exact structures were determined by X-ray dif-
fraction analysis as 15 for tribromide and 16 for tetrabromide
(Fig. 2). The conformation and location of bromine and the methoxy
groups is shown in Fig. 2.
Fig. 1. The molecular structures of bromophenols 12e14. Displacement ellipsoids are shown at the 50% probability level.

3486
Y. C¸ etinkaya et al. / Tetrahedron 67 (2011) 3483e3489
O
OMe
Br
O
OMe
Br
O
OMe
OMe
OMe
OMe
OMe
Br
OMe
OMe
Br2 (6 equiv.)
+
Fe/HOAc
MeO
MeO
Br
MeO
Br
Reflux/5 h
OMe
OMe
Br
OMe
Br
Br
6
15
16
19%
5%
+
Br
OMe
Br
Br
O
Br
Br
OMe
OMe
Br
OMe
+
+
OMe
MeO
Br
18
OMe
Br
63%
17
Scheme 5.
Fig. 2. The molecular structures of bromides 15 and 16. Displacement ellipsoids are shown at the 50% probability level.
-
H
-
H
Br
O
Br
+
+
OMe
O
OMe
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
HBr
R
R
R
Br
Br
Br
19
20
21
-
Br
-
H
Br
H
Me
Me
OMe
+
O
O
OH
O
O
O
+
OMe
OMe
OMe
OMe
R
R
R
OMe
-MeBr
Br
Br
Br
12-14
23
22
Scheme 6.

Y. C¸ etinkaya et al. / Tetrahedron 67 (2011) 3483e3489
3487
3. Conclusion
4.3. Standard procedure for the selective bromination of
ketone 6 with LiBr/CAN: synthesis of (5-bromo-2,3,4-
trimethoxyphenyl)(3,4-dimethoxyphenyl) methanone (9)
(3,4-Dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methanone (6)
was obtained from the reaction of acid 7 and 1,2,3-trimethox-
ybenzene (8) in PPA. Depending upon the number of equiva-
lents of LiBr/CAN and 6 at rt, monobromide 9 and dibromide 10
were obtained as the sole products while products with more
Br than the two were not obtained. The formation of bromi-
nated all products with Br 9e14 from ketone 6 and molecular
Br2 depend on different conditions such as the number of
equivalents of Br2 and time, temperatures and catalyst of the
reaction.
Bromophenols 12e14 were formed during brominations of
ketone 6 with Br2. It was accepted that bromophenols 12e14 were
formed from the reactions of corresponding bromides (19) with
HBr by selective O-demethylation. To our knowledge, selective
O-demethylation during bromination is not known. By this method,
aromatic compounds, such as ketone 6 including CO groups may be
converted into corresponding bromophenols.
To a solution of 6 (332 mg, 1 mmol) and LiBr (96 mg, 1.1 mmol) in
CH3CN (15 mL) was added a solution of CAN (0.60 g, 1.1 mmol) in
CH3CN (15 mL) dropwise at room temperature (rt) and under nitro-
gen (N2) over 10 min. After the solutionwas stirred at rt and under N2
for 3 days, water (15 mL) was added and the mixture was extracted
with EtOAc (2ꢃ30 mL). The organic phasewas washedwith solutions
(5%, 2ꢃ15 mL) of NaHCO3, water (2ꢃ15 mL), and brine (15 mL). Then
it was dried over Na2SO4 and the solvents were evaporated. Mono-
bromide 9 (401 mg, 97%), the sole product, was crystallized from
ethyl acetate/hexane as colorless block crystals. Mp 136e138 ꢀC; Rf
(14.3%, EtOAc/hexane) 0.15; dH (400 MHz, CDCl3) 7.54 (d, J¼2.0 Hz,
aromatic, 1H), 7.27 (dd, A part of AB-system, J¼2.0, 8.4 Hz, aromatic,
1H), 7.24 (s, aromatic, 1H), 6.85 (d, B part of AB-system, J¼8.4 Hz,
aromatic, 1H), 3.96 (s, OCH3, 3H), 3.94 (s, OCH3, 6H), 3.93 (s, OCH3,
3H), 3.77 (s, OCH3, 3H); dC (400 MHz, CDCl3) 192.9 (CO), 154.0 (C),
153.1 (C),151.9 (C),149.3 (C),147.7 (C),130.9 (C),130.4 (C),126.9 (CH),
126.3 (CH), 111.6 (C), 111.1 (C), 110.1 (CH), 62.2 (OCH3), 61.4 (OCH3),
61.4 (OCH3), 56.33 (OCH3), 56.26 (OCH3). nmax (CH2Cl2, cmꢂ1): 3067,
2934, 2861, 1660, 1593,1513,1462, 1415,1238, 1163, 1147, 1084, 1046,
917; MS m/z (CI, methane) 411.0/413.0 (97/94, Mþ). Anal. Calcd for
(C18H19BrO6): C 52.57, H 4.66. Found C 52.40, H 4.65.
4. Experimental
4.1. General
All chemicals and solvents are commercially available and
were used after distillation or treatment with drying agents.
Melting points were determined on a capillary melting apparatus
(BUCHI 530) and are uncorrected. IR spectra were obtained from
solutions in 0.1 mm cells with a PerkineElmer spectrophotome-
ter. The 1H and 13C NMR spectra were recorded on a 200 (50) and
4.4. Synthesis of (5-bromo-2,3,4-trimethoxyphenyl)(3-
bromo-4,5-dimethylphenyl)methanone (10)
This reaction was performed according to standard procedure
described in that of 9. In this reaction, the moles of 6, CAN and LiBr
used were 1.0, 2.2 and 2.2, respectively. After chromatography (SiO2,
80 g) with EtOAc/hexane (1:6), dibromide 10 (417 mg, 87%, brown
liquid), and monobromide 9 (63 mg, 13%) were obtained. Rf (14.3%,
EtOAc/hexane) 0.19; (5-bromo-2,3,4-trimetylphenyl)(3-bromo-4,5-
dimetylphenyl)methanone (10): dH (400 MHz, CDCl3) 7.43 (s, aromatic,
1H), 6.99 (s, aromatic, 1H), 6.95 (s, aromatic, 1H), 3.94 (s, OCH3, 3H),
3.88 (s, OCH3, 3H), 3.83(s, OCH3, 3H), 3.82 (s, OCH3, 3H), 3.64 (s, OCH3,
3H); dC (400 MHz, CDCl3) 193.0 (CO), 154.9 (C), 153.5 (C), 151.7 (C),
148.4 (C), 147.5 (C), 133.4(C), 129.8 (CH), 128.8 (CH), 116.2 (CH), 113.2
(C), 112.0 (C), 111.7 (C), 61.8 (OCH3), 61.4 (OCH3), 61.3 (OCH3), 56.5
(OCH3), 56.4 (OCH3); nmax (CH2Cl2, cmꢂ1): 2939, 2842, 1661, 1593,
1506, 1461, 1404, 1376, 1334, 1295, 1261, 1218, 1166, 1094, 1056, 1030,
999, 939; MS m/z (CI, methane) 488.9/490.9/493.0 (51/100/48, Mþ).
Anal. Calcd for (C18H18Br2O6): C 44.11, H 3.70. Found C 43.92, H 3.69.
Only, dibromide 10 was obtained when the reaction of 6
(1.0 mmol) with CAN (6.0 mmol) and LiBr (6.0 mmol) was per-
formed according to standard procedure described in that of 9.
400 (100)-MHz Varian spectrometer;
d in parts per million, Me4Si
as the internal standard. Elemental analyses were performed on
a Leco CHNS-932 apparatus. All column chromatography was
performed on silica gel (60-mesh, Merck). PLC is preparative
thick-layer chromatography: 1 mm of silica gel 60 PF (Merck) on
glass plates.
4.2. Synthesis of (3,4-dimethoxyphenyl)(2,3,4-
dimethoxyphenyl)methanone (6)
Polyphosphoric acid (PPA), which was prepared from concd
H3PO4 (85%, 16.0 g) and P2O5 (28.2 g, 0.2 mol), was heated to 80 ꢀC
in a beaker (150 mL) and mixed. To this mixture were added tri-
methoxybenzene (4.62 g, 27.5 mmol) and 7 (5.0 g, 27.5 mmol)
quickly. The mixture was stirred with a glass stick at 80 ꢀC for
1.5 h and then was carefully poured onto 35 mL of ice/water. The
organic phase was extracted with ethyl acetate (EtOAc)
(2x125 mL). The combined organic layers were dried over Na2SO4
and the solvent was evaporated. Ketone 6 (9.1 g, 94%) was the sole
product and was crystallized from EtOAc/hexane as colorless
block crystals. Mp 117e119 ꢀC: dH (400 MHz, CDCl3), 7.51 (br d,
J¼2.0 Hz, aromatic, 1H), 7.29 (dd, A part of AB-system, J¼2.0,
8.4 Hz, aromatic, 1H), 7.06 (d, A part of AB-system, J¼8.6 Hz, 1H),
6.83 (d, B part of AB-system, J¼2.0 Hz, J¼8.4 Hz, aromatic, 1H),
6.70 (d, B part of AB-system, J¼8.6 Hz, aromatic, 1H), 3.92 (s,
OCH3, 3H), 3.91 (s, OCH3, 3H), 3.90 (s, OCH3, 3H), 3.88 (s, OCH3,
3H), 3.76 (s, OCH3, 3H); dC (400 MHz, CDCl3) 194.3 (CO), 155.9
(CH), 153.5 (C), 152.5 (C), 149.1 (C), 142.3 (C), 131.3 (C), 127.0 (C),
125.8 (CH), 124.7 (CH), 111.5 (C), 110.0 (CH), 107.0 (CH), 62.1
(OCH3), 61.2 (OCH3), 56.3 (OCH3), 56.3 (OCH3), 56.2 (OCH3); nmax
(CH2Cl2, cmꢂ1): 2943, 2839, 1646, 1593, 1514, 1496, 1462, 1417,
1273, 1183, 1140, 1097, 1055, 1037, 1021, 988, 920. Anal. Calcd for
(C18H20O6): C 65.05, H 6.07. Found C 64.79, H 6.06.
4.5. Reaction of ketone 6 with bromine in different
conditions
4.5.1. Bromination of ketone 6 by 1.1 equiv bromine at rt. To a stir-
ring solution of ketone 6 (1.0 g, 3.0 mmol, 1 equiv) in CHCl3 (40 mL)
was added a solution of bromine (530 mg, 3.3 mmol, 1.1 equiv) in
CHCl3 (20 mL) dropwise at rt over 10 min. After the reaction mix-
ture was stirred at rt for 1 day, the solvent was evaporated. Mon-
obromide 9 (401 mg, 96%), the sole product, was crystallized from
ethyl acetate/hexane.
4.5.2. Bromination of ketone 6 by 2.2 equiv bromine at rt. To a stir-
red solution of ketone 6 (1.0 g, 3.0 mmol, 1.0 equiv) in CHCl3
(50 mL) was added a solution of bromine (1.06 g, 6.6 mmol,
2.2 equiv) in CHCl3 (10 mL) dropwise at rt over 5 min. The mixture
was stirred at the same temperature for 2.5 days, the solvent was
evaporated, and chromatography of the residue on silica gel (SiO2,

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Y. C¸ etinkaya et al. / Tetrahedron 67 (2011) 3483e3489
110 g) with ethyl acetate/hexane (1:6) gave the dibromide 10
(340 mg, 23%) and monobromide 9 (880 mg, 71%), respectively.
2937, 2841, 1624, 1580, 1544, 1478, 1445, 1419, 1372, 1320, 1260,
1214, 1125, 1054, 1035, 987, 961; MS m/z (CI, methane) 552.9/554.9/
556.9/558.9 (34/100/97/32, Mþ). Anal. Calcd for (C17H15Br3O6): C
36.79, H 2.72. Found C 36.90, H 2.73.
4.5.3. Bromination of ketone 6 by 6.0 equiv bromine at reflux in
CHCl3. To a stirring solution of ketone 6 (2.0 g, 6.0 mmol) in CHCl3
(50 mL) was added a solution of bromine (36 mmol, 5.77 g,
6.0 equiv) in CHCl3 (20 mL) dropwise at rt over 10 min. After the
reaction mixture was stirred and refluxed for 3 days, the reaction
mixture was cooled to rt and the solvent was evaporated. The
residue was subjected to column chromatography on silica gel
(SiO2, 110 g) and eluted using EtOAc/hexane (1:6) to give the tri-
bromophenol 14 (52 mg, 1.6%), tribromophenol 13 (200 mg, 6%),
dibromophenol 12 (1.95 g, 68%), dibromide 10 (472 mg, 20%), and
dibromide 11 (55 mg, 1.9%). All products 11e14 except for 10 (liq-
uid) were crystallized from ethyl acetate/hexane.
4.5.8. Bromination of ketone 6 by 10.0 equiv bromine at reflux in
CHCl3. Reaction of ketone
6 (2.0 g, 6.0 mmol) with bromine
(60 mmol, 9.6 g, 10.0 equiv) in CHCl3 (50 mL) and separation of the
residue were performed according to standard procedure described
in 4.4.3. Tribromophenol 14 (68 mg, 2.1%), tribromophenol 13
(367 mg, 11%), dibromophenol 12 (2.12 g, 74%), dibromide 10
(71 mg, 3%), and dibromide 11 (43 mg, 1.5%) were obtained.
4.5.9. Bromination by 10.0 equiv bromine at rt. To a stirred solution
of ketone 6 (1.0 g, 3.0 mmol, 1.0 equiv) in CHCl3 (50 mL) was added
a solution of bromine (9.64 g, 30.0 mmol, 6.0 equiv) in CHCl3
(10 mL) dropwise at rt over 10 min. The mixture was stirred at the
same temperature for 8 days, the solvent was evaporated, and
chromatography of the residue on silica gel (SiO2, 110 g) with
EtOAc/hexane (1:6) gave the tribromophenol 14 (40 mg, 2.4%),
tribromophenol 13 (217 mg, 13%), dibromophenol 12 (1.05 g, 73%),
dibromide 10 (30 mg, 2%), and dibromide 11 (20 mg, 1.4%).
4.5.4. (2,3-Dibromo-4,5,6-trimethoxyphenyl)(3,4-dimethoxyphenyl)
methanone (11). Colorless block crystals; mp 141e143 ꢀC; Rf (14.3%,
EtOAc/hexane) 0.14; dH (400 MHz, CDCl3) 7.62 (d, 1H, J¼1.8 Hz,
aromatic, 1H), 7.20 (dd, A part of AB-system, J¼1.9 Hz, J¼8.4 Hz,
aromatic, 1H), 6.84 (d, B part of AB-system, J¼8.4 Hz, aromatic, 1H),
3.96 (s, OCH3, 3H), 3,95 (s, OCH3, 3H), 3,94 (s, OCH3, 6H), 3,77 (s,
OCH3, 3H); dC (400 MHz, CDCl3) 191.8 (CO),154.5 (C), 153.1 (C), 151.0
(C), 149.7 (C), 146.9 (C), 133.1 (C), 129.4 (C), 126.1 (CH), 116.9 (C),
115.7 (C), 110.6 (CH), 110.4 (CH), 62.1 (OCH3), 61.4 (2 OCH3), 56.3
(OCH3), 56.3 (OCH3); nmax (CH2Cl2, cmꢂ1): 2937, 2854, 1665, 1593,
1513, 1460, 1418, 1399, 1296, 1270, 1206, 1164, 1142, 1094, 1021, 999;
MS m/z (CI, methane) 488.9/490.9/492.9 (51/100/48, Mþ). Anal.
Calcd for (C18H18Br2O6): C 44.11, H 3.70. Found C 44.11, H 3.3.71.
4.5.10. Standard procedure for bromination of ketone 6 by catalytic
Fe at reflux in AcOH for 6 h. To a stirred at reflux mixture of ketone 6
(1.0 g, 3.0 mmol,1.0 equiv) and powder Fe (240 mg) in AcOH (50 mL)
was added a solution of bromine (5.44 g, 69.0 mmol, 6.0 equiv) in
AcOH (10 mL) dropwise at rt over 10 min. The mixture was stirred
and heated at reflux for 5 h. After the mixture was cooled to rt and it
was poured onto mixture (600 g) of water and ice, the mixture with
water was waited for 1 days. Solid was filtered and washed CH2Cl2
(300 mL). The combined organic layers were dried over Na2SO4 and
the solvent was evaporated. Chromatography of the residue on silica
gel (SiO2, 90 g) with EtOAc/hexane (1:6) gave known 18 (710 mg,
63%), tetrabromide 16 (380 mg,19%) and tribromide 15 (120 mg, 7%).
The products 15 and 16 were crystallized from ethyl acetate/hexane.
4.5.5. (5-Bromo-2-hydroxy-3,4-dimethoxyphenyl)(2-bromo-4,5-
dimethoxyphenyl)methanone (12). Colorless block crystals; mp
143e146 ꢀC; Rf (14.3%, EtOAc/hexane) 0.35; dH (400 MHz, CDCl3)
12.27 (s, OH, 1H), 7.26 (s, aromatic, 1H), 7.11 (s, aromatic, 1H), 6.81
(s, aromatic, 1H), 4.09 (s, OCH3, 3H), 3.98 (s, OCH3, 3H), 3.96
(s, OCH3, 3H), 3,88 (s, OCH3, 3H); dC (400 MHz, CDCl3) 199.5 (CO),
158.5 (C), 156.6 (C), 151.3 (C), 148.6 (C), 141.8 (C), 131.8 (CH), 130.9
(C), 116.8 (C), 116.1 (CH), 111.7 (CH), 110.5 (C), 106.1 (C), 61.5 (OCH3),
61.3 (OCH3), 56.6 (OCH3), 56.5 (OCH3); nmax (CH2Cl2, cmꢂ1): 3011,
2943, 2837, 2047, 1749, 1631, 1507, 1476, 1442, 1409, 1311, 1261,
1206, 1168, 1108, 1052, 1028, 987, 964, 912; MS m/z (CI, methane)
474.9/476.9/478.9 (51/100/48, Mþ). Anal. Calcd for (C17H16Br2O6):
C 42.89, H 3.39. Found C 42.78, H 3.40.
4.5.11. (2-Bromo-4,5-dimethoxyphenyl)-(2,3-dibromo-4,5,6-trime-
thoxyphenyl)-methanone (15). Colorless block crystals; mp
102e104 ꢀC; Rf (14.3%, EtOAc/hexane) 0.22; dH (400 MHz, CDCl3)
7.39 (s, aromatic, 1H), 7.08 (s, aromatic, 1H), 3.95 (s, OCH3, 3H), 3.93
(s, OCH3, 3H), 3.91 (s, OCH3, 3H), 3.8 (s, OCH3, 3H), 3.77 (s, OCH3,
3H); dC (400 MHz, CDCl3) 190.9 (CO), 153.6 (C), 153.3 (C), 151.2 (C),
148.6 (C),146.9 (C),133.7 (C),129.1 (C),117.4 (C),117.1 (CH),116.2 (C),
115.2 (C), 114.9 (CH), 61.9 (OCH3), 61.5 (OCH3), 61.3 (OCH3) 56.6
(OCH3), 56.5 (OCH3); nmax (CH2Cl2, cmꢂ1): 3006, 2946, 2840, 1649,
1586,1507,1455,1395,1371,1342,1299,1267,1205,1161,1067,1090,
1035, 1020, 1002, 936; MS m/z (CI, methane) 566.9/568.9/570.9/
572.9 (36/100/94/33, Mþ). Anal. Calcd for (C18H17Br3O6): C 37.99, H
3.01. Found C 37.91, H 3.00.
4.5.6. (5-Bromo-2-hydroxy-3,4-dimethoxyphenyl)(2,3-dibromo-4,5-
dimethoxyphenyl)methanone (13). Colorless block crystals; mp
128e130 ꢀC; Rf (14.3%, EtOAc/hexane) 0.42; dH (400 MHz, CDCl3)
12.12 (s, OH, 1H), 7.17 (s, 1H), 6.80 (s, aromatic, 1H), 4.09 (s, OCH3,
3H), 3.97 (s, OCH3, 3H), 3.94 (s, OCH3, 3H), 3,87 (s, OCH3, 3H); dC
(400 MHz, CDCl3) 198.7 (CO), 158.6 (C), 156.9 (C), 153.0 (C), 149.4
(C), 141.9 (C), 135.9 (C), 131.3 (CH), 123.2 (C), 116.3 (C), 112.9 (C),
111.19 (CH), 106.5 (C), 61.6 (OCH3), 61.4 (OCH3), 60.9 (OCH3), 56.7
(OCH3); nmax (CH2Cl2, cmꢂ1): 2998, 2940, 2848,1626,1545,1475,1415,
1373, 1323, 1295, 1256, 1204, 1166, 1127, 1063, 1035, 1002, 968, 915;
MS m/z (CI, methane) 552.9/554.9/556.9/558.9 (35/100/97/32, Mþ).
Anal. Calcd for (C17H15Br3O6): C 36.79, H 2.72. Found C 36.84, H 2.71.
4.5.12. (2,3-Dibromo-4,5-dimethoxyphenyl)-(2,3-dibromo-4,5,6-tri-
methoxyphenyl)-methanone (16). Colorless block crystals; mp
113e115 ꢀC; Rf (14.3%, EtOAc/hexane) 0.33; dH (400 MHz, CDCl3)
7.25 (s, aromatic, 1H), 3.94 (s, OCH3, 3H), 3.91 (s, OCH3, 3H), 3.90 (s,
OCH3, 3H), 3.85 (s, OCH3, 3H), 3.72 (s, OCH3, 3H); dC (400 MHz,
CDCl3) 191.5 (CO), 153.9 (C), 152.3 (C), 151.4 (C), 151.1 (C), 146.8 (C),
135.2 (C), 133.1 (C), 124.5 (C), 117.4 (C), 116.5 (C), 116.5 (C), 115.1 (C),
62.0 (OCH3), 61.5 (OCH3), 61.3 (OCH3), 61.0 (OCH3), 56.6 (OCH3);
nmax (CH2Cl2, cmꢂ1): 3077, 2979, 2939, 2844, 1673, 1579, 1554, 1462,
1401, 1304, 1200, 1161, 1105, 1078, 1041, 993, 940, 909; MS m/z (CI,
methane) 644.8/646.8/648.8/650.8/652.8 (18/71/100/64/17, Mþ).
Anal. Calcd for (C18H16Br4O6): C 33.37, H 2.49. Found C 33.29, H 2.48.
4.5.7. (5-Bromo-2-hydroxy-3,4-dimethoxyphenyl)(2,6-dibromo-3,4-
dimethoxyphenyl)methanone (14). Pale yellow block crystals; mp
122e125 ꢀC; Rf (14.3%, EtOAc/hexane) 0.47; Rf (14.3%, EtOAc/hex-
ane) 0.47; dH (400 MHz, CDCl3) 12.06 (s, OH, 1H), 7.14 (s, aromatic,
1H), 7.10 (s, aromatic, 1H), 4.03 (s, OCH3, 3H), 3.98 (s, OCH3, 3H),
3.95, (s, OCH3, 3H), 3.89 (s, OCH3, 3H); dH (400 MHz, CDCl3) 197.6
(CO), 158.5 (C), 156.8 (C), 154.8 (C), 146.6 (C), 141.9 (C), 132.2 (C),
130.5 (CH), 116.6 (C), 116.3 (CH), 116.0 (C), 114.0 (C), 106.6 (C), 61.5
(OCH3), 61.4 (OCH3), 61.0 (OCH3), 56.7, (OCH3); nmax (CH2Cl2, cmꢂ1):
4.5.13. 1,2,3-Tribromo-4,5-dimethoxybenzene (18). White solid; mp
82e84 ꢀC (lit.10a 86 ꢀC); Rf (14.3%, EtOAc/hexane) 0.81; dH

Y. C¸ etinkaya et al. / Tetrahedron 67 (2011) 3483e3489
3489
(400 MHz, CDCl3) 7.19 (s, aromatic, 1H), 3.86 (s, OCH3, 3H), 3.83 (s,
OCH3, 3H); dC (400 MHz, CDCl3) 153.0 (C), 147.3 (C), 122.4 (C), 119.9
(C), 118.7 (C), 116.6, (CH) 60.8 (OCH3), 56.7 (OCH3).
F2: 1.202; final R indices [I>2
s
(I)]: R1¼0.061, wR2¼0.100; R indices
(all data): R1¼0.084, wR2¼0.109; largest diff. peak and hole: 0.313
ꢀꢂ3
and ꢂ0.558 e A ; CCDC: 800314. Crystal data for 15: C18H17O6Br3,
crystal system, space group: orthorhombic, P212121 ; unit cell di-
ꢀ
4.5.14. Bromination of ketone 6 by catalytic Fe at reflux in AcOH for
1.5 h. This reaction was performed according to the standard pro-
cedure described in 4.5.1. To a stirred at reflux mixture of ketone 6
(0.5 g, 1.5 mmol, 1.0 equiv) and powder Fe (120 mg) in AcOH
(25 mL) was added a solution of bromine (2.72 g, 38.5 mmol,
6.0 equiv) in AcOH (5 mL) dropwise at rt over 10 min. The mixture
was stirred and heated at reflux for 1.5 h. The 1H NMR spectrum of
the reaction mixture was performed and the percent age of com-
pounds 15, 16, and 18 was found to be 7, 32, and 61, respectively.
mensions: aꢀ¼7.7998 (2), b¼9.3736 (3), c¼27.7532 (4) A,
a¼90,
3
ꢀ
b
¼90,
g
¼90 ; volume: 2029.10 (4) A ; Z¼4; calculated density:
1.86 mg/m3; absorption coefficient: 5.995 mmꢂ1; F(000): 1112;
q-
range for data collection 2.3e26.4ꢀ; refinement method: full-matrix
least-square on F2; data/parameters: 3076/244; goodness-of-fit on
F2: 1.076; final R indices [I>2
s
(I)]: R1¼0.049, wR2¼0.072; R indices
(all data): R1¼0.077, wR2¼0.079; largest diff. peak and hole: 0.301
ꢀꢂ3
and ꢂ0.424 e A ; CCDC: 800254. Crystal data for 16: C18H16O6Br4,
crystal system, space group: triclinic, Pꢂ1; unit cell dimensions:
ꢀ
a¼9.0333 (2), b¼ꢀ 9.5828 (2), c¼13.2203 (4) A,
a
¼73.38 (2), ¼74.66
b
3
ꢀ
4.6. Crystallography
(4),
g
¼76.03 (4) ; volume: 1040.44 (5) A ; Z¼2; calculated density:
2.07 mg/m3; absorption coefficient: 7.796 mmꢂ1; F(000): 624;
q-
For the crystal structure determination, a single-crystal of the
bromophenols 12e16 was used for data collection on a four-circle
Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-di-
range for data collection 2.4e26.4ꢀ; refinement method: full-matrix
least-square on F2; data/parameters: 3066/253; goodness-of-fit on
F2: 1.112; final R indices [I>2
s
(I)]: R1¼0.054, wR2¼0.097; R indices
mensional area IP detector). The graphite-monochromatized Mo K
a
(all data): R1¼0.083, wR2¼0.114; largest diff. peak and hole: 0.628
ꢀ
ꢀꢂ3
radiation (
l
¼0.71073 A) and oscillation scans techniquewith Du¼5ꢀ
and ꢂ0.516 e A ; CCDC: 801841.
for one image were used for data collection. The lattice parameters
were determined by the least-squares methods on the basis of all
reflections with F2>2 (F2). Integration of the intensities, correction
s
Acknowledgements
for Lorentz and polarization effects and cell refinement was per-
formed using CrystalClear (Rigaku/MSC Inc., 2005) software.12 The
structures were solved by direct methods using SHELXS-9713 and
refined by a full-matrix least-squares procedure using the program
SHELXL-97.13 Hydrogen positions were found from difference
Fourier maps and geometric calculations and refined using a riding
model. The final difference Fourier maps showed no peaks of
chemical significance. Crystal data for 12: C17H16O6Br2, crystal sys-
The authors are indebted to the Department of Chemistry and
€
Ataturk University for financial support of this work (Project No.:
BAB-2009/84).
References and notes
1. (a) Gribble, G. W. J. Nat. Prod. 1992, 55, 1353e1395; (b) Gribble, G. W. Chem. Soc.
Rev. 1999, 28, 335e346; (c) Gribble, G. W. Environ. Sci. Pollut. Res. Int. 2000, 7,
37e49.
2. (a) Lee, H. S.; Lee, T. H.; Lee, J. H.; Chae, C. S.; Chung, S. C.; Shin, D. S.; Shin, J.; Oh,
K. B. J. Agric. Food Chem. 2007, 55, 6923e6928; (b) Shi, D. Y.; Xu, F.; He, J.; Jing,
L.; Li, J.; Fan, X.; Han, L. J. Chin. Sci. Bull. 2008, 53, 2476e2479.
3. Xu, X.; Song, F.; Wang, S.; Li, S.; Xiao, F.; Zhao, J.; Yang, Y.; Shang, S.; Yang, L.; Shi,
J. J. Nat. Prod. 2004, 67, 1661e1666.
4. Kurata, K.; Taniguchii, K.; Takashima, K.; Hayashi, I.; Suzuki, M. Phytochemistry
1997, 45, 485e487.
5. (a) Oh, K.-B.; Lee, J. H.; Chung, S. C.; Shin, J.; Shin, H. J.; Kim, H. K.; Lee, H. S.
Bioorg. Med. Chem. Lett. 2008, 18, 104e108; (b) Xu, N.; Fan, X.; Yan, X.; Li, X.; Niu,
R.; Tseng, C. K. Phytochemistry 2003, 62, 1221e1224.
tem, space group: monoclinic, P21/n; unit cell dimensions: a¼9.458
ꢀ
(2), b¼17.685 (3), c¼10.523(4) A,
a¼90,
b
¼94.35 (3),
g
¼90ꢀ; vol-
3
ꢀ
3
ume: 1755.04 (2) A ; Z¼4; calculated density: 1.80 mg/m ; ab-
sorption coefficient: 4.650 mmꢂ1; F(000): 944;
q-range for data
collection 2.3e30.6ꢀ; refinement method: full-matrix least-square
on F2; data/parameters: 4600/232; goodness-of-fit on F2: 1.527;
final R indices [I>2
s
(I)]: R1¼0.086, wR2¼0.135; R indices (all data):
R1¼0.140, wR2¼0.140; largest diff. peak and hole: 0.504 and
ꢀꢂ3
ꢂ0.490 e A ; CCDC: 800677. Crystal data for 13: C17H15O6Br3,
crystal system, space group: monoclinic, P21c; unit cell dimensions:
6. (a) Balaydın, H. T.; Gulcin, I.; Menzek, A.; Goksu, S.; Sahin, E. J. Enzyme Inhib.
Med. Chem. 2010, 25, 685e695; (b) Duan, X. J.; Li, X. M.; Wang, B. G. J. Nat. Prod.
2007, 70, 1210e1213.
7. Wang, W.; Okada, Y.; Shi, H.; Wang, Y.; Okuyama, T. J. Nat. Prod. 2005, 68,
620e622.
ꢀ
a¼12.774 (2), b¼12.3020 (3), c¼12.8680(4) A,
a
¼90, ¼109.60(3),
b
3
ꢀ
3
ꢀ
g
¼90 ; volume: 1904.9 (4) A ; Z¼4; calculated density: 1.93 mg/m ;
absorption coefficient: 6.383 mmꢂ1; F(000): 1080;
q-range for data
collection 3.2e26.6ꢀ; refinement method: full-matrix least-square
8. (a) Kubo, I.; Ochi, M.; Shibata, K.; Hanke, F. J.; Nakatsu, T.; Tan, K. S. J. Nat. Prod.
on F2; data/parameters: 2200/237; goodness-of-fit on F2: 1.124; final
€
1990, 53, 50e56; (b) S¸ engul, M. E.; Menzek, A.; Balcı, M. Turk. J. Chem. 2006, 30,
€
131e138; (c) Balaydın, H. T.; Akbaba, Y.; Menzek, A.; S¸ ahin, E.; Goksu, S. Arkivoc
R indices [I>2
s
(I)]: R1¼0.093, wR2¼0.153; R indices (all data):
€
2009, XIV, 75e87; (d) Akbaba, Y.; Balaydın, H. T.; Goksu, S.; S¸ ahin, E.; Menzek,
R1¼0.176, wR2¼0.191; largest diff. peak and hole: 0.992 and
A. Helv. Chim. Acta 2010, 93, 1127e1135.
ꢀꢂ3
9. Roy, S. C.; Guin, C.; Rana, K. K.; Maiti, G. Tetrahedron Lett. 2001, 42, 6941e6942.
10. (a) Frejka, J.; Sefranek, B. Collect. Czech. Chem. Commun. 1936, 8, 130e139; (b)
Kohn, M.; Steiner, L. J. Org. Chem. 1947, 12, 30e33.
11. (a) Elix, J. A.; Jiang, H. Aust. J. Chem. 1990, 43, 1591e1595; (b) Sharghi, H.;
Tamaddon, F. Tetrahedron 1996, 52, 13623e13640; (c) Liu, T.; Huazhou Ying, H.;
Lin, G.; Hu, Y. Synth. Commun. 2008, 38, 1815e1821.
ꢂ0.902 e A ; CCDC: 800857. Crystal data for 14: C17H15O6Br3,
crystal system, space group: triclinic, Pꢂ1; unit cell dimensions:
ꢀ
a¼8.6515 (2), b¼10.4691 (3), c¼11.7338 (4) A,
a
¼73.71 (3), ¼79.35
b
3
ꢀ
(3),
g
¼77.12 (3)ꢀ ; volume: 985.89 (4) A ; Z¼2; calculated density:
1.87 mg/m3; absorption coefficient: 6.167 mmꢂ1; F(000): 540;
q-
12. Rigaku/MSC, 9009 new Trails Drive, The Woodlands, TX 77381.
range for data collection 2.4e26.4ꢀ; refinement method: full-matrix
least-square on F2; data/parameters: 3122/235; goodness-of-fit on
€
13. Sheldrick, G. M. SHELXS97 and SHELXL97; University of Gottingen: Germany,
1997.