Synthesis of hydroxylated and methoxylated polybrominated diphenyl ethers - Natural products and potential polybrominated diphenyl ether metabolites

Article abstract of DOI:10.1002/ejoc.200300081

Hydroxylated and methoxylated polybrominated diphenyl ethers (OH-PBDEs and MeO-PBDEs) may be natural products or they may be formed as metabolites of polybrominated diphenyl ethers (PBDEs), frequently used as flame retardants. The aim of this work was to synthesize authentic OH- and MeO-PBDE reference standards for analytical and toxicological studies. Brominated phenoxybenzaldehydes were prepared either by coupling of 2,4-dibromophenol with various fluorobenzaldehydes or by coupling of brominated hydroxybenzaldehydes with 2,2′,4,4′-tetrabromodiphenyliodonium chloride. OH-PBDEs were synthesized via the brominated phenoxybenzaldehydes by Baeyer-Villiger oxidation and acid-catalyzed hydrolysis. These OH-PBDEs were ortho- and para-brominated (relative to the hydroxy group) with benzyltrimethylammonium tribromide and/or orthobrominated with bromine/tert-butylamine, and were also brominated with bromine in one case. MeO-PBDEs were obtained by methylation of the prepared OH-PBDEs. MeO-PBDEs were also prepared through the coupling of brominated methoxyphenols with 2,2′,4,4′-tetrabromodiphenyliodonium salts, the corresponding OH-PBDEs being obtained after demethylation. A majority of the OH-/MeO-PBDEs prepared have the hydroxy/methoxy group in the ortho position relative to the diphenyl ether bond. All OH-/MeO-PBDEs prepared have 2,4-dibromo substitution patterns (relative to the diphenyl ether bond) in the non-hydroxy-/non-methoxy-containing ring. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300081

FULL PAPER
Synthesis of Hydroxylated and Methoxylated Polybrominated Diphenyl Ethers
؊ Natural Products and Potential Polybrominated Diphenyl Ether Metabolites
[a]
[b]
[a]
˚
Göran Marsh,* Roland Stenutz, and Ake Bergman
Keywords: Aromatic substitution / Halogenation / Natural products / Oxidations / Polybrominated diphenyl ethers
Hydroxylated and methoxylated polybrominated diphenyl
ethers (OH-PBDEs and MeO-PBDEs) may be natural prod- brominated with bromine in one case. MeO-PBDEs were ob-
ucts or they may be formed as metabolites of polybrominated tained by methylation of the prepared OH-PBDEs. MeO-
diphenyl ethers (PBDEs), frequently used as flame retard- PBDEs were also prepared through the coupling of bromin-
ants. The aim of this work was to synthesize authentic OH- ated methoxyphenols with 2,2Ј,4,4Ј-tetrabromodiphenyl-
and MeO-PBDE reference standards for analytical and tox- iodonium salts, the corresponding OH-PBDEs being obtained
icological studies. Brominated phenoxybenzaldehydes were after demethylation. A majority of the OH-/MeO-PBDEs pre-
prepared either by coupling of 2,4-dibromophenol with vari- pared have the hydroxy/methoxy group in the ortho position
brominated with bromine/tert-butylamine, and were also
ous fluorobenzaldehydes or by coupling of brominated hy-
droxybenzaldehydes with 2,2Ј,4,4Ј-tetrabromodiphenyl-
iodonium chloride. OH-PBDEs were synthesized via the bro-
relative to the diphenyl ether bond. All OH-/MeO-PBDEs
prepared have 2,4-dibromo substitution patterns (relative to
the diphenyl ether bond) in the non-hydroxy-/non-methoxy-
minated phenoxybenzaldehydes by Baeyer−Villiger oxida- containing ring.
tion and acid-catalyzed hydrolysis. These OH-PBDEs were
ortho- and para-brominated (relative to the hydroxy group)
with benzyltrimethylammonium tribromide and/or ortho-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
The aim of this work was to synthesize authentic OH-
PBDEs and MeO-PBDEs for identification of those com-
pounds present in biota, and to make it possible to assess
their toxicity. All OH- and MeO-PBDEs were prepared so
as to have a 2,4-dibromo substitution pattern (relative to
the diphenyl ether bond) in the non-hydroxy-/non-methoxy-
containing ring. This substitution pattern is consistent with
all OH- and MeO-PBDEs previously found as natural
products containing two bromine atoms in the non-hy-
droxylated/non-methoxylated ring,[1,2] although it should
also be mentioned that 2-bromo[18,19] and 4-bromo substi-
tution patterns[20] have also been reported. Moreover, the
dominating bromine substitution in manmade PBDEs con-
taining two bromine atoms in one of the phenyl rings is also
the 2,4-dibromo-substitution pattern,[15] although 3,4- and
2,5-dibromo-substitution is also known.[21] All known nat-
urally occurring OH- and MeO-PBDEs are hydroxy-/meth-
oxy-substituted ortho to the diphenyl ether bond. In con-
trast, the hydroxy groups in 2,2Ј,4,4Ј-tetrabromodiphenyl
ether metabolites seem to be situated at any of the ortho-,
meta-, or even para-positions.[13]
Hydroxylated polybrominated diphenyl ethers (OH-
PBDEs) and methoxylated polybrominated diphenyl ethers
(MeO-PBDEs) are known natural products that have been
reported to occur in marine species such as sponges,[1Ϫ3]
ascidians (tunicates),[4,5] and green alga.[6] Recently, these
two groups of substances have also been reported in species
at higher trophic levels. MeO-PBDEs were found in
fish,[7Ϫ9] turtles,[10] birds,[11] and marine mammals.[7,10] OH-
PBDEs were reported in fish[8] and humans.[12]
OH-PBDEs have also been identified as metabolites of
2,2Ј,4,4Ј-tetrabromodiphenyl ether in mice and rats[13] and
in fish.[14] 2,2Ј,4,4Ј-Tetrabromodiphenyl ether is generally
the most abundant PBDE contaminant in humans and
wildlife.[15] Another environmentally relevant PBDE con-
gener, 2,2Ј,4,4Ј,5-pentabromodiphenyl ether, has also been
shown to form hydroxylated metabolites in rats.[16] PBDEs
are used as flame retardants in polymers, rubber, and tex-
tiles, and several PBDE congeners have been identified as
widespread environmental pollutants.[15,17]
The synthesis of some MeO-PBDEs and OH-PBDEs
have previously been published, the OH-PBDEs having
been obtained in these cases by demethylation of the MeO-
PBDEs with BBr3.[22,23] Brominated 2-methoxyphenols
have been coupled with halonitrobenzenes to give nitro-
MeO-PBDEs. The nitro group was reduced and the re-
[a]
Department of Environmental Chemistry, Stockholm
University,
10691 Stockholm, Sweden
[b]
Department of Organic Chemistry, Stockholm University,
10691 Stockholm, Sweden
Fax: (internat.) ϩ 46-8/163979
E-mail: goran.marsh@mk.su.se
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DOI: 10.1002/ejoc.200300081
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Synthesis of Hydroxylated and Methoxylated Polybrominated Diphenyl Ethers
FULL PAPER
sulting amino group was replaced with bromine through
diazotization and either Sandmeyer reaction or treatment
with copper() bromide.[23,24] MeO-PBDEs have also been
prepared by the coupling of brominated diphenyliodonium
iodides with brominated 2-methoxyphenols.[22]
In this work, a modification of the last method has been
used for the synthesis of some OH-PBDEs and MeO-
PBDEs. However, the majority of the OH- and MeO-
PBDEs were prepared via brominated phenoxybenzal-
dehydes by conversion of the aldehyde group into a hydroxy
group by BaeyerϪVilliger oxidation and hydrolysis. The
OH-PBDEs obtained were brominated in the ortho and
para positions and/or in the ortho position relative to the
hydroxy group. Finally MeO-PBDEs were prepared by
methylation of the corresponding OH-PBDEs.
Scheme 2. Coupling of 2,4-dibromophenol with fluorobenzal-
dehydes; DMAC ϭ N,N-dimethylacetamide
We also used BaeyerϪVilliger oxidation and acid-cata-
lyzed hydrolysis for the preparation of OH-PBDEs 12Ϫ16,
with the brominated phenoxybenzaldehydes 1Ϫ2 and 6Ϫ8
as precursors (Scheme 3). Phenoxybenzaldehyde 6 could be
oxidized to the corresponding formate ester with m-CPBA
(in CHCl3 at 30 °C), whereas phenoxybenzaldehyde 2 was
unreactive to this agent. Only 50% of the phenoxybenzal-
dehyde 8 was converted into the formate after 10 h by m-
CPBA (in CHCl3 at 30 °C). However, all the brominated
phenoxybenzaldehydes were completely oxidized by trifluo-
roperacetic acid (TFPA), and so this agent was used for all
these oxidations in this work, with use of KH2PO4 as buffer.
In the absence of buffer, side reactions such as ether cleav-
age and rearrangements were observed. To minimize side-
reactions further, the reaction temperature was kept at 0 °C
except in the oxidation of phenoxybenzaldehyde 2, which
was carried out at room temperature.
The OH-PBDEs 17Ϫ19 were prepared from OH-PBDEs
14Ϫ16 by bromination ortho to the hydroxy groups. This
was achieved by the method of Pearson et al.[33] by addition
of bromine to tert-butylamine in toluene at Ϫ30 °C, fol-
lowed by addition of the OH-PBDE in CH2Cl2 to the bro-
mine/tert-butylamine complex at Ϫ70 °C (Scheme 3). The
reaction mixture was not allowed to warm up to room tem-
perature in this case, however, but was kept between Ϫ60
°C and Ϫ65 °C throughout the reaction. The reaction was
quenched by addition of water/ethanol (1:9 v/v) simul-
taneously with passage of a stream of sulfur dioxide
through the reaction mixture. Using these conditions the
yield of para-brominated product never exceeded 1%
whereas the ortho-para-dibrominated product was not
formed. These precautions were necessary since the pre-
viously described procedure[33] had given not only the de-
sired ortho-bromo product but also the para-bromo and di-
bromo products, which decreased the yields and compli-
cated the purification of the desired products. Unchanged
Results and Discussion
Brominated phenoxybenzaldehydes, precursors to the
majority of the OH- and MeO-PBDEs with the hydroxy/
methoxy group in the ortho position to the diphenyl ether
bond, were prepared by two different diphenyl ether coup-
ling reactions. In the first coupling, the brominated phenox-
ybenzaldehydes 1Ϫ2 were prepared by treatment of
2,2Ј,4,4Ј-tetrabromodiphenyliodonium chloride 3 with the
brominated 2-hydroxybenzaldehydes 4 and 5, respectively,
in aqueous NaOH/dioxane (Scheme 1). Several halodiphen-
yliodonium chlorides have previously been coupled with
different
halogenated
2-methoxyphenols[22,25,26]
or
phenols[26Ϫ29] with water as the only solvent. The use of
dioxane as a co-solvent improved solubility and resulted in
higher yields. The benzaldehyde 4 was prepared by ortho-
formylation of phenols as described by Hofsløkken and
Skattebøl,[30] whereas the benzaldehyde 5 was commer-
cially available.
Scheme 1. Coupling of 2,2Ј,4,4Ј-tetrabromodiphenyliodonium
chloride with brominated 2-hydroxybenzaldehydes
In the other diphenyl ether coupling, the brominated starting material was recovered in all these reactions.
phenoxybenzaldehydes 6Ϫ8 were prepared by substitution Dibrominations ortho and para to the hydroxy groups of
of fluorobenzaldehydes 9Ϫ11 (commercially available) with OH-PBDEs 12Ϫ15 gave the OH-PBDEs 20Ϫ23 and were
2,4-dibromophenol (Scheme 2). This coupling has been re- carried out in CH2Cl2/MeOH solution with use of benzyl-
ported previously for the synthesis of various monosubsti- trimethylammonium
tribromide
(BTMA-Br3)[34,35]
tuted phenoxybenzaldehydes, which were converted into hy- (Scheme 3). To avoid ether cleavage of the OH-PBDEs dur-
droxylated diphenyl ethers via BaeyerϪVilliger oxidation ing the bromination, the BTMA-Br3 had to be added in
with meta-chloroperbenzoic acid (m-CPBA) followed by small portions over several hours and in the presence of
acid-catalyzed hydrolysis.[31,32]
calcium carbonate.
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G. Marsh, R. Stenutz, A. Bergman
FULL PAPER
Scheme 4. Preparation of OH- and MeO-PBDEs by coupling of
2,2Ј,4,4Ј-tetrabromodiphenyliodonium iodide with brominated 2-
methoxyphenols; DMAC ϭ N,N-dimethylacetamide
2,3,4-Tribromo-6-methoxyphenol 36 was prepared by
treatment of 2-methoxyphenol with an excess of bromine in
acetic acid, without any other brominated 2-methoxyphenol
congeners being observed. When this reaction was per-
formed with 3 equivalents of bromine as described by Rai-
ford and Silker,[37] dibrominated 2-methoxyphenols (15%,
assessed by GC-MS) were obtained besides the desired
product 36. 2-Methoxyphenol in a mixture with CaCO3 has
previously been solid-phase perbrominated with bromine,
Scheme 3. OH- and MeO-PBDEs prepared by BaeyerϪVilliger oxi- giving 2,3,4,5-tetrabromo-6-methoxyphenol 37 in 97%
yield.[22] However, because of difficulties in stirring during
dation and subsequent hydrolysis of brominated 2-phenoxybenzal-
dehydes, followed by bromination; BTMA-Br3 ϭ benzyltrimeth-
the reaction, this procedure gave 30% di- and tribrominated
2-methoxyphenols (as estimated by GCϪMS) in our hands.
Use of a slight excess of bromine and an ultrasonic bath
were more advantageous to us. The pathway for the prep-
aration of 5-chloro-2,4-dibromo-6-methoxyphenol 35 is
shown in Scheme 5 and each step for the preparation of
hydroxybenzaldehyde 45, methoxybenzaldehyde 46, and
methoxyphenol 47 includes methods described above.
ylammonium tribromide
The MeO-PBDEs 24Ϫ33 were prepared by use of iodo-
methane as described previously.[36]
The couplings of the brominated 2-methoxyphenols
34Ϫ37 with iodonium iodide 38 were carried out in the
presence of K2CO3 and 18-crown-6 in N,N-dimethylaceta-
mide (DMAC), giving MeO-PBDEs 29 and 39Ϫ41 in
49Ϫ60% yield (Scheme 4). This route, with the synthesis
performed in aqueous NaOH, had been reported earlier[22]
for the preparation of 40Ϫ41 in 52% and 67% yields, respec-
tively, but in our hands this procedure resulted in lower
yields (29% and 22%, respectively), despite fewer observed
side-reactions. When the 2-methoxyphenols 34 and 36 were
used in the coupling with the iodonium chloride 3, compli-
cated mixtures of products were obtained irrespective of the
method applied.
The HO-PBDEs 16 and 42Ϫ44 were prepared from the
corresponding MeO-PBDEs 29 and 39Ϫ41 by use of BBr3
in CH2Cl2.[22,23] We found that elevated temperatures (50
°C) were necessary in order to achieve acceptable reaction
times in the demethylation of MeO-PBDEs.
The synthesis of 2,2Ј,4,4Ј-tetrabromodiphenyliodonium
chloride 3 was slightly modified from that previously de-
scribed,[27] and the preparation of the iodide analogue 38
was based on this methodology. Iodonium iodide 38 has
been reported previously,[22] but the experimental con-
Scheme 5. Preparation of 5-chloro-2,4-dibromo-6-methoxyphenol
(35), the precursor to MeO-PBDE 39; BTMA-Br3 ϭ benzyltri-
methylammonium tribromide
OH-PBDEs and the corresponding MeO-PBDEs with
ditions and chemical characterization of the product were the hydroxy/methoxy group in the meta position relative to
not provided. the ether oxygen were prepared as shown in Schemes 6 and
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Synthesis of Hydroxylated and Methoxylated Polybrominated Diphenyl Ethers
FULL PAPER
7. The phenoxybenzaldehyde 48 was prepared as for the drolysis converted the aldehyde 57 into the OH-PBDE 58.
MeO-PBDEs 29 and 39Ϫ41 above, but with the iodonium Monobromination of OH-PBDE 58, by use of 1 equiv. bro-
chloride 3 instead of the iodonium iodide 38 (Scheme 6). In mine in acetic acid, gave the desired tetrabrominated OH-
aqueous NaOH/dioxane this reaction gave lower yields and PBDEs 59Ϫ60 as well as the pentabrominated OH-PBDE
more side reactions such as C-arylation [i.e., two com- 61, but some unchanged starting material was also reco-
pounds (not isolated) with four-bromine isotope patterns vered. When the bromination was carried out in CH2Cl2/
and [Mϩ] ϭ 558]. The benzaldehyde 48 was converted into MeOH with 1 equiv. BTMA-Br3, smaller amounts of tetra-
the corresponding OH-PBDE 49 by BaeyerϪVilliger oxi- brominated OH-PBDEs 59Ϫ60 were observed, with more
dation and hydrolysis as described above for the prep- OH-PBDE 61 and unchanged OH-PBDE 58. We were not
aration of OH-PBDE 12Ϫ16. Dibromination in the two po- able to separate the OH-PBDEs 59Ϫ60 in this step, but they
sitions ortho to the hydroxy group of the OH-PBDE 49 could be separated from OH-PBDEs 58 and 61 on silica
generated two major products (Scheme 6), the tribromin- gel. These last two compounds were methylated to give the
ated OH-PBDE 50 being isolated besides the desired prod- MeO-PBDEs 62 and 63. The former mixture of OH-PBDE
uct 51. One additional monobrominated compound and 59 and 60 was methylated, the two MeO-PBDEs 64Ϫ65
one dibrominated compound were also detected by were separated, and each of the pure OH-PBDEs 59 and
GCϪMS. These side-products were estimated to amount to 60 was recovered after demethylation.
less than 2% by GCϪMS and could be separated from the
products on silica. Methylation of OH-PBDEs 50Ϫ51 gave
MeO-PBDEs 52Ϫ53. Further OH- and MeO-PBDE com-
pounds with the hydroxy/methoxy groups meta to the di-
phenyl ether bond were prepared by coupling of 2,4-di-
bromo-5-methoxyphenol 54[35] with iodonium chloride 3
(Scheme 7) as described above for the brominated phenoxy-
benzaldehydes 1Ϫ2. Demethylation of the obtainedMeO-
PBDE 55 gave the corresponding OH-PBDE 56.
Scheme 8. Pathway for the preparations of OH-PBDEs and MeO-
PBDEs with the hydroxy/methoxy group in the para-position to the
diphenyl ether bond; DMAC ϭ N,N-dimethylacetamide
Full-scan electron ionization mass spectrometry (EIMS)
Scheme 6. Pathway for the preparation of OH-PBDEs with the
showed two abundant ions for all OH-PBDEs: the molecule
ion [M]ϩ and the fragment ion [M Ϫ 2 Br]ϩ. OH-PBDEs
with a hydroxy group ortho to the diphenyl ether bond gave
the ion [C6H4Br2]ϩ. The fragment ion showed increasing
intensity with number of halogen atoms on the hydroxy-
substituted ring. This fragment ion is most probably formed
by ether cleavage and hydrogen transfer as previously re-
ported.[20,38] The MeO-PBDEs generated more fragment
ions than the OH-PBDEs. All MeO-PBDEs gave the fol-
hydroxy group in the meta-position to the diphenyl ether bond;
DMAC ϭ N,N-dimethylacetamide
Scheme 7. Pathway for the preparation of a MeO-PBDE with the
methoxy group in the meta-position to the diphenyl ether
bond
lowing abundant ions: [M]ϩ, [M
Ϫ Ϫ
2 Br]ϩ, [M
2 BrCH3]ϩ, and [M Ϫ 2 BrCH3CO]ϩ. The ortho-substituted
MeO-PBDEs gave a characteristic [M Ϫ BrCH3]ϩ fragment
The synthesis of OH- and MeO-PBDEs with the ion, which was not formed in the cases of the meta- and
hydroxy/methoxy groups para to the diphenyl ether bond para-substituted MeO-PBDEs. The para-substituted MeO-
are shown in Scheme 8. The phenoxybenzaldehyde 57 was PBDEs gave characteristic [M Ϫ CH3]ϩ fragment ions,
prepared by coupling of 3-bromo-4-fluoro-benzaldehyde which could not be detected for the ortho- and meta-substi-
and 2,4-dibromophenol. BaeyerϪVilliger oxidation and hy- tuted MeO-PBDEs. This characteristic fragmentation is
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G. Marsh, R. Stenutz, A. Bergman
FULL PAPER
6.5 mL) was added dropwise to iodine (5.4 g, 21 mmol). A mixture
of concd. sulfuric acid (1.7 mL), fuming sulfuric acid (65%,
0.8 mL), and fuming nitric acid (100%, 3.0 mL) was added drop-
wise over 30 min, and the reaction mixture was stirred at 75 °C for
2 h, during which time yellow crystals of iodylsulfate precipitated.
The reaction mixture was diluted with concd. sulfuric acid (20 mL),
and 1,3-dibromobenzene (25 g, 106 mmol) was added over 30 min
at 10Ϫ15 °C. The mixture was stirred at 40 °C for 12 h. Water
(100 mL) was carefully added in small portions, with cooling in a
water ice bath, and the formed nitrogen oxides were removed by a
stream of nitrogen gas. After standing at 8 °C for 15 h, the clear
aqueous solution was decanted off and the crude product was dis-
solved in MeOH (300 mL). Concd. hydrochloric acid (5 mL) in
consistent with methoxylated polychlorinated diphenyl
ethers (MeO-PCDEs)[39,40] as well as methoxylated polych-
lorinated biphenyls (MeO-PCBs).[41,42]
Conclusion
Twenty OH-PBDEs and their corresponding MeO-
PBDEs containing three to six bromine atoms have been
synthesized and characterized by EIMS and 1H NMR spec-
troscopy. Additionally, three OH-PBDEs were prepared as
precursors. Three of the OH-PBDEs and two of the MeO-
PBDEs prepared contain a chlorine atom. All these com- MeOH (10 mL) was added dropwise, and the crystallized chloride
3 was filtered off and washed with MeOH, toluene, and water.
Yield 23.0 g, 87%. Decomposes at 167Ϫ168 °C (ref.[27] 164Ϫ165
°C). 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ ϭ 7.69 (dd,
pounds are required as authentic reference standards for
identification/quantification of the corresponding chemicals
in the environment, being natural components in biota or
metabolites of PBDEs. Most of the OH-PBDEs were ob-
tained from oxidized and hydrolyzed brominated phenoxy-
benzaldehydes, which were further brominated, and finally
3
4J3-H,5-H ϭ 2.2, J5-H,6-H ϭ 8.6, 2 H, 5-H), 8.16 (d, 2 H, 3-H), 8.31
(d, 2 H, 6-H) ppm.
2,2Ј,4,4Ј-Tetrabromodiphenyliodonium Iodide (38): This compound
the OH-PBDEs were methylated and isolated as the corre- was prepared as described for 3, but was crystallized by dropwise
addition of potassium iodide (10 g, 60 mmol) in water (10 mL).
sponding MeO-PBDEs. The preparation of certain OH-
and MeO-PBDEs by this route is a good alternative to pre-
viously described methods.
Yield 25.8 g, 85%. Decomposes at 115؊120 °C. 1H NMR
4
(400 MHz, [D6]DMSO, 25 °C): δ ϭ 7.74 (dd, J3-H,5-H ϭ 2.2,
3J5-H,6-H ϭ 8.6, 2 H, 5-H), 8.21 (d, 2 H, 3-H), 8.36 (d, 2 H, 6-
H) ppm.
Experimental Section
2,3,4-Tribromo-6-methoxyphenol (36): 2-Methoxyphenol (0.50 g,
4.0 mmol) in acetic acid (4 mL) was treated gradually with bromine
(32 mmol, 1.64 mL) in acetic acid (4 mL) over 6 h. After 0.5 h,
when approximately one equivalent of bromine had been added,
the reaction temperature was raised from room temperature to 35
°C and a gentle stream of nitrogen was allowed to pass through
the reaction vessel to remove the hydrobromic acid formed. The
reaction mixture was kept at a volume of Ն 4 mL by addition of
acetic acid. After the last addition of bromine the reaction mixture
was stirred for an additional hour. The product crystallized when
the reaction mixture was cooled to room temperature, and the
crude product was dissolved in CH2Cl2 (40 mL) and washed with
water (40 mL), aqueous NaHSO3 (5%, 2 ϫ 40 mL), and water (2
ϫ 40 mL). The crude product was chromatographed on a silica gel
column, eluting with n-hexane/ethyl acetate, 2:1. Yield 1.37 g, 95%.
General Remarks: Melting points were determined on a Büchi 353
apparatus and were not corrected. 1H NMR spectra (400 MHz)
were recorded on a Varian Mercury 400 spectrometer in CDCl3
solution (15 mg/mL) at 25 °C with TMS (δH ϭ 0.00 ppm) as in-
ternal standard unless stated otherwise. Most of the PBDEs and
their derivatives gave easily interpreted 1H NMR spectra with
characteristic coupling patterns (3JH,H ഠ 7Ϫ9 Hz and JH,H
ഠ
4
2 Hz). In some cases in which it was not possible to assign the
resonances from their coupling patterns, selective irradiation
experiments were performed in order to assign resonances to one
of the two aromatic rings. Assignment of the OH resonances in the
2-hydroxybenzaldehydes was confirmed by exchange with D2O.
Mass spectrometry electron ionization (EIMS) was performed on
a quadrupole TSQ 700 Finnigan MAT instrument connected with
a Varian 3400 gas chromatograph, with helium as the carrier gas.
The electron energy was 70 eV and the ion source temperature was
150 °C.
1
M.p. 116Ϫ117 °C (ref.[37] 115Ϫ116 °C). H NMR: δ ϭ 3.91 (s, 3
H, OCH3), 6.07 (br. s, 1 H, OH), 7.13 (s, 1 H, 5-H) ppm. EIMS:
m/z [ion] (rel. int.%) 360 [M ϩ 2]ϩ (100), 345 [M Ϫ CH3 ϩ 2]ϩ
(54), 317 [M Ϫ CH3CO ϩ 2]ϩ (24).
2,3,4,5-Tetrabromo-6-methoxyphenol (37): CaCO3 (2.0 g, 20 mmol)
was added in small portions and with careful stirring to 2-meth-
oxyphenol (0.62 g, 5.0 mmol). Bromine (50 mmol, 2.56 mL) was
added dropwise, after which the reaction mixture was allowed to
stand in an ultrasonic bath for 1 h at room temperature. Excess
bromine was removed by use of a stream of nitrogen. The crude
product was dissolved in CH2Cl2 (30 mL), filtered, and washed
with aqueous NaHSO3 (5%, 30 mL) and water (2 ϫ 30 mL). The
crude product was chromatographed on a silica gel column, eluted
with n-hexane/ethyl acetate, 3:1. Yield 1.9 g, 86%. M.p. 162Ϫ163
°C (ref.[22] 162Ϫ162.5 °C). 1H NMR: δ ϭ 3.92 (s, 3 H, OCH3), 6.11
(br. s, 1 H, OH) ppm. EIMS: m/z [ion] (rel. int.%) 440 [M ϩ 4]ϩ
(100), 425 [M Ϫ CH3 ϩ 4]ϩ (64), 397 [M Ϫ CH3CO ϩ 4]ϩ (28).
Except for the iodonium salts, all prepared compounds had a purit-
ies of Ͼ 98% according to GCϪMS. Silica gel column chromatog-
˚
raphy was carried out on MATREX Silica (60 A, 35Ϫ70 µm, Milli-
pore, Bedford, USA). Except for the two tetrabromodiphenyliodon-
ium salts (3 and 38), all organic extracts were dried with anhydrous
sodium sulfate. Organic solutions were concentrated in a rotary
evaporator under reduced pressure at temperatures not exceeding
35 °C. Solutions containing iodomethane were concentrated in a
hood at 30 °C under a stream of nitrogen. Compounds 4,[30] 34,[34]
45,[30] and 54[35] were prepared by literature procedures without any
significant modifications. All other reagents and solvents (including
compounds 5 and 9Ϫ11) were used as obtained from commercial
sources without further purification, except for 2,4-dibromophenol,
which was purified by recrystallization (water/ethanol 3:1).
Coupling of 2,2Ј,4,4Ј-Tetrabromodiphenyliodonium Salts with 3-
Hydroxybenzaldehyde and Brominated 2-Methoxyphenols: 2,2Ј,4,4Ј-
Tetrabromodiphenyliodonium iodide 38 (2.2 g, 3.0 mmol) was ad-
2,2Ј,4,4Ј-Tetrabromodiphenyliodonium Chloride (3): A mixture of
concd. sulfuric acid (13.0 mL) and fuming sulfuric acid (65%,
2570
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2566Ϫ2576

Synthesis of Hydroxylated and Methoxylated Polybrominated Diphenyl Ethers
FULL PAPER
1
Table 1. H NMR data for the aldehydes
Aldehyde ring
4
2Ј,4Ј-Dibromo ring
Coupling constants
2
3
5
6
3Ј
5Ј
6Ј
CHO
10.14
1[a]
OAr
Br
7.95[b]
7.33
7.93[b]
7.81
7.26
6.28
3J4-H,5-H ϭ 7.9; J4-H,6-H ϭ 1.6; J5-H,6-H ϭ 7.9;
4
3
5J5-H,CHO ϭ 0.9; J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
4
3
3
2
6
OAr
OAr
Br
6.75
8.05
7.52
Br
7.22
8.05
7.96
7.81
7.83
7.28
7.45
6.29
6.94
10.06
10.50
4J3Ј-H,5Ј-H ϭ 2.6; J5Ј-H,6Ј-H ϭ 8.8
4
3
3J3-H,4-H ϭ 8.2; J3-H,5-H ϭ 1.1; J4-H,5-H ϭ 7.3;
3
5
4J4-H,6-H ϭ 1.8; J5-H,6-H ϭ 7.7; J5-H,CHO ϭ 0.8;
4J3Ј-H,5Ј-H ϭ 2.2; J5Ј-H,6Ј-H ϭ 8.8
3
4
3
7
OAr
OAr
7.37
Cl
7.75[b]
7.58
7.39
Br
7.91[b]
8.05
7.81
7.83
7.81
7.27
7.48
7.44
6.31
6.97
6.91
10.17
10.49
9.97
3J4-H,5-H ϭ 7.8; J4-H,6-H ϭ 1.6; J5-H,6-H ϭ 7.9;
5J5-H,CHO ϭ 0.7; J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
4
4
8[a]
48
6.62
OAr
3J3-H,4-H ϭ 8.8; J4-H,6-H ϭ 2.6; J3Ј-H,5Ј-H ϭ 2.5;
3J5Ј-H,6Ј-H ϭ 8.7
7.25[b]
7.52
7.62[b]
4J2-H,4-H ϭ 1.4; J2-H,6-H ϭ 2.5; J4-H,5-H ϭ 7.5;
4
3
3
4
4J4-H,6-H ϭ 1.1; J5-H,6-H ϭ 8.0; J3Ј-H,5Ј-H ϭ 2.3;
3J5Ј-H,6Ј-H ϭ 8.6
3
4
57
8.18
Br
OAr
6.96
7.74
7.84
7.49
6.76
9.90
4J2-H,6-H ϭ 1.8; J5-H,6-H ϭ 8.6; J3Ј-H,5Ј-H ϭ 2.4;
3J5Ј-H,6Ј-H ϭ 8.5
[a]
[b]
Assignment verified by selective irradiation experiments. Tentative assignment Ϫ chemical shifts may be interchanged.
ded to a solution of the brominated 2-methoxyphenols or 3-
phenoxybenzaldehyde (2.5 mmol), 18-crown-6 (0.13 g, 0.5 mmol),
(100), 578 [M Ϫ BrCH3 ϩ 4]ϩ (45), 514 [M Ϫ 2 Br ϩ 4]ϩ (74), 499
1
[M Ϫ 2 BrCH3 ϩ 4]ϩ (15), 471 [M Ϫ 2 BrCH3CO ϩ 4]ϩ (22). H
and suspended K2CO3 (0.69 g, 5.0 mmol) in DMAC (30 mL), and NMR: see Table 3.
the reaction mixture was stirred at 80 °C for 1 h. 2,2Ј,4,4Ј-Tetrabro-
Coupling of 2,2Ј,4,4Ј-Tetrabromodiphenyliodonium Chloride with
Brominated 2-Hydroxybenzaldehydes and 4,6-Dibromo-3-meth-
oxyphenol: 2,2Ј,4,4Ј-Tetrabromodiphenyliodonium chloride
modiphenyliodonium chloride 3 (1.9 g, 3.0 mmol) was used for the
preparation of compound 48. The mixture was diluted with CH2Cl2
(30 mL), and water (30 mL) was added. The organic layer was sepa-
rated, and the water layer was extracted with CH2Cl2 (30 mL). The
combined organic layers were washed with aqueous NaHSO3 (5%,
50 mL), aqueous NaOH (1 , 3 ϫ 50 mL), and water (2 ϫ 50 mL).
Purification was performed on a silica gel column.
3
(1.9 g, 3.0 mmol) was added to a solution of the brominated
hydroxybenzaldehyde or methoxyphenol (2.5 mmol) and NaOH
(0.12 g, 3.0 mmol) in water (15 mL) and dioxane (15 mL), and the
reaction mixture was stirred at 80 °C for 1Ϫ8 h. CH2Cl2 (50 mL)
and water (40 mL) were added to the reaction mixture. The organic
layer was separated and washed with aqueous NaOH (1 , 3 ϫ
50 mL) and water (3 ϫ 50 mL). The crude product was purified by
silica gel chromatography.
3-(2,4-Dibromophenoxy)benzaldehyde (48): This compound was
prepared from 3-hydroxybenzaldehyde (0.31 g, 2.5 mmol). The sil-
ica gel eluent was CH2Cl2/n-hexane, 2:1. Yield 0.80 g, 90% as an
oil. EIMS: m/z [ion] (rel. int.%) 356 [M ϩ 2]ϩ (52), 168 [M Ϫ
3-Bromo-2-(2,4-dibromophenoxy)benzaldehyde (1): This compound
was prepared from 4 (0.50 g, 2.5 mmol), with a reaction time of
8 h. The silica gel eluent was n-hexane/CH2Cl2, 1:1. Yield 0.87 g,
80%. M.p. 111.5Ϫ112.5 °C. EIMS: m/z [ion] (rel. int.%) 434 [M ϩ
1
2 BrCO]ϩ (100). H NMR: see Table 1.
3,5-Dibromo-2-(2,4-dibromophenoxy)anisole (29): This compound
was prepared from 34[34] (0.70 g, 2.5 mmol). The silica gel eluent
was n-hexane/CH2Cl2, 3:1. Yield 0.63 g, 49%. M.p. 115Ϫ116 °C
(ref.[23] 116.5Ϫ117.5 °C). EIMS: m/z [ion] (rel. int.%) 516 [M ϩ 4]ϩ
(100), 420 [M Ϫ BrCH3 ϩ 2]ϩ (23), 356 [M Ϫ 2 Br ϩ 2]ϩ (28), 341
1
2]ϩ (23), 355 [M Ϫ Br ϩ 2]ϩ (38), 198 [M Ϫ C6H4Br2]ϩ (100). H
NMR: see Table 1.
1
[M Ϫ 2 BrCH3 ϩ 2]ϩ (7), 313 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (18). H
3,5-Dibromo-2-(2,4-dibromophenoxy)benzaldehyde (2): This com-
pound was prepared from 5 (0.70 g, 2.5 mmol), with a reaction time
of 4 h. The silica gel eluent was n-hexane/CH2Cl2, 3:2. Yield 1.16 g,
90%. M.p. 168Ϫ169 °C. EIMS: m/z [ion] (rel. int.%) 514 [M ϩ 4]ϩ
NMR: see Table 3.
3,5-Dibromo-6-chloro-2-(2,4-dibromophenoxy)anisole (39): This
compound was prepared from 35 (0.79 g, 2.5 mmol). The silica gel
eluent was n-hexane/CH2Cl2, 4:1. Yield 0.82 g, 60%. M.p. 67Ϫ68.5
°C. EIMS: m/z [ion] (rel. int.%) 550 [M ϩ 4]ϩ (100), 456 [M Ϫ
BrCH3 ϩ 4]ϩ (43), 390 [M Ϫ 2 Br ϩ 2]ϩ (45), 375 [M Ϫ 2 BrCH3
ϩ 2]ϩ (7), 347 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (21). 1H NMR: see Table 3.
1
(21), 433 [M Ϫ Br ϩ 2]ϩ (25), 278 [M Ϫ C6H4Br2 ϩ 2]ϩ (100). H
NMR: see Table 1.
4,6-Dibromo-3-(2,4-dibromophenoy)anisole (55): This compound
was prepared from 54[35] (0.70 g, 2.5 mmol), with a reaction time
of 1 h. The silica gel eluent was n-hexane/CH2Cl2, 3:1. Yield 1.17 g,
91%. M.p. 141.5Ϫ142.5 °C. EIMS: m/z [ion] (rel. int.%) 516 [M ϩ
4]ϩ (76), 356 [M Ϫ 2 Br ϩ 2]ϩ (100), 341 [M Ϫ 2 BrCH3 ϩ 2]ϩ
3,4,5-Tribromo-2-(2,4-dibromophenoxy)anisole (40): This com-
pound was prepared from 36 (0.90 g, 2.5 mmol). The silica gel elu-
ent was n-hexane/CHCl3, 3:1. Yield 0.88 g, 59%. M.p. 155.5Ϫ156.5
°C (ref.[22] 158Ϫ159 °C). EIMS: m/z [ion] (rel. int.%) 594 [M ϩ 4]ϩ
(100), 500 [M Ϫ BrCH3 ϩ 4]ϩ (29), 434 [M Ϫ 2 Br ϩ 2]ϩ (41), 419
1
(58), 313 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (26). H NMR: see Table 3.
Coupling of 2,4-Dibromophenol with Fluorobenzaldehydes: 2,4-Di-
bromophenol (5.0Ϫ8.0 mmol, 1 equiv.) and the fluorobenzaldehyde
(1 equiv.) were dissolved in DMAC (6Ϫ10 mL). Anhydrous
Na2CO3 (1 equiv.) was added, and the reaction mixture was heated
at reflux for 1Ϫ3 h. CH2Cl2 (30 mL) and water (50 mL) were added
1
[M Ϫ 2 BrCH3 ϩ 2]ϩ (11), 391 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (19). H
NMR: see Table 3.
3,4,5,6-Tetrabromo-2-(2,4-dibromophenoxy)anisole (41): This com-
pound was prepared from 37 (1.1 g, 2.5 mmol). The silica gel eluent
was n-hexane/CH2Cl2, 6:1. Yield 0.82 g, 49%. M.p. 105.5Ϫ106.5 °C to the cooled reaction mixture, and the organic layer was separated
(ref.[22] 119Ϫ120 °C). EIMS: m/z [ion] (rel. int.%) 674 [M ϩ6]ϩ
and washed with aqueous NaOH (1 , 2 ϫ 30 mL) and water (2
Eur. J. Org. Chem. 2003, 2566Ϫ2576
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2571

˚
G. Marsh, R. Stenutz, A. Bergman
FULL PAPER
1
Table 2. H NMR spectroscopic data for the OH-PBDEs
Phenol ring
4
2Ј,4Ј-Dibromo ring
3Ј 5Ј 6Ј OH
coupling constants
2
3
5
6
4
3
12 OAr 6.77Ϫ6.79 (m, 1 H), 6.82Ϫ6.87 (m, 1 H), 7.06Ϫ7.08 (m, 2 H)
7.78 7.38 6.84 5.54 J3Ј-H,5Ј-H ϭ 2.2; J5Ј-H,6Ј-H ϭ 8.8
3
4
13 OAr Cl
7.01[a]
7.12
7.00[a]
7.77 7.27 6.45 5.46 J4-H,5-H ϭ 8.2; J4-H,6-H ϭ 1.6;
3J5-H,6-H ϭ 8.2; J3Ј-H,5Ј-H ϭ 2.3;
4
3J5Ј-H,6Ј-H ϭ 8.8
3
4
14 OAr Br
7.18[a]
7.05
7.03[a]
7.78 7.27 6.43 5.42 J4-H,5-H ϭ 7.7; J4-H,6-H ϭ 1.8;
3J5-H,6-H ϭ 8.4; J3Ј-H,5Ј-H ϭ 2.4;
4
3J5Ј-H,6Ј-H ϭ 8.8
3
4
15 OAr 6.74
16 OAr Br
17 OAr Br
18[b] OAr 6.66
6.96
Br
7.22
7.22[a]
Br
7.79 7.40 6.61 5.65 J3-H,4-H ϭ 8.5; J4-H,6-H ϭ 2.5;
4J3Ј-H,5Ј-H ϭ 2.2; J5Ј-H,6Ј-H ϭ 8.8
3
4
4
7.33[a]
7.31[a]
7.16
Br
7.79 7.29 6.44 5.65 J4-H,6-H ϭ 2.2; J3Ј-H,5Ј-H ϭ 2.3;
3J5Ј-H,6Ј-H ϭ 8.8
3
4
7.11[a]
Br
7.77 7.31 6.41 5.72 J4-H,5-H ϭ 8.8; J3Ј-H,5Ј-H ϭ 2.4;
3J5Ј-H,6Ј-H ϭ 8.8
3
4
Br
7.79 7.40 6.83 6.02 J3-H,4-H ϭ 8.8; J3Ј-H,5Ј-H ϭ 2.4;
3J5Ј-H,6Ј-H ϭ 8.6
4
3
19 OAr Br
20 OAr 6.81
7.55
Br
Br
7.44
Br
Br
7.78 7.28 6.42 5.91 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
4
7.82 7.45 6.90 5.31 J3-H,5-H ϭ 2.1; J3Ј-H,5Ј-H ϭ 2.3;
3J5Ј-H,6Ј-H ϭ 8.6
4
3
21 OAr Cl
22 OAr Br
23 OAr 7.01
42 OAr Br
43 OAr Br
44 OAr Br
49 6.44 OAr
Br
Br
Br
7.53
Br
7.73
7.74
Br
Br
Br
Br
7.18
Br
Br
Br
Cl
7.78 7.29 6.42 5.75 J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.6
4
3
7.78 7.28 6.39 5.75 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
7.81 7.45 6.89 6.04 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.6
4
3
7.78 7.28 6.42 5.85 J3Ј-H,5Ј-H ϭ 2.2; J5Ј-H,6Ј-H ϭ 8.8
4
3
7.44
Br
7.79 7.30 6.41 5.62 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
Br
7.79 7.29 6.40 5.90 J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
4
4
6.52[a]
6.59[a]
7.77 7.38 6.87 4.83 J2-H,4-H ϭ 2.3; J2-H,6-H ϭ 2.3;
3J4-H,5-H ϭ 8.2; J4-H,6-H ϭ 0.9;
4
3J5-H,6-H ϭ 8.2; J3Ј-H,5Ј-H ϭ 2.4;
4
3J5Ј-H,6Ј-H ϭ 8.6
4
3
50[b] 6.60 OAr
6.44
6.31
7.39
7.38
Br
Br
7.78 7.41 6.89 5.54 J2-H,4-H ϭ 2.7; J4-H,5-H ϭ 8.8;
4J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.6
3
3
4
51 Br
OAr
7.79 7.39 6.78 6.05 J4-H,5-H ϭ 8.9; J3Ј-H,5Ј-H ϭ 2.4;
3J5Ј-H,6Ј-H ϭ 8.7
4
3
56 6.47[a] OAr
58 7.15 Br
Br
OAr
7.71[a]
6.90
Br
6.79
7.79 7.41 6.80 5.50 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.7
4
3
7.75 7.29 6.52 4.82 J2-H,6-H ϭ 2.9; J5-H,6-H ϭ 8.8;
4J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
3
3
4
59 Br
Br
OAr
7.03[a]
6.93[a]
7.77 7.31 6.54 5.56 J5-H,6-H ϭ 8.9; J3Ј-H,5Ј-H ϭ 2.3;
3J5Ј-H,6Ј-H ϭ 8.7
4
3
60 Br
61 Br
7.33[a]
Br
OAr
OAr
Br
7.12
7.09[a]
Br
7.77 7.33 6.60 5.42 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
7.79 7.36 6.63 5.92 J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
[a]
[b]
Tentative assignment Ϫ chemical shifts may be interchanged. Assignment verified by selective irradiation experiments.
ϫ 30 mL). The crude product was purified by silica gel chromatog-
raphy.
gel chromatography, eluting with n-hexane/ethyl acetate, 7:1. Yield
1.85 g, 85%. M.p. 129Ϫ130 °C. EIMS: m/z [ion] (rel. int.%) 434 [M
ϩ 2]ϩ (22), 355 [M Ϫ Br ϩ 2]ϩ (44), 198 [M Ϫ C6H4Br2]ϩ (100).
1H NMR: see Table 1.
2-(2,4-Dibromophenoxy)benzaldehyde (6): This compound was pre-
pared from 9 (0.62 g, 5.0 mmol) in DMAC (6 mL), with a reaction
time of 3 h. The crude product, an oil, was distilled under reduced
pressure at 135 °C and then chromatographed on silica gel with
CH2Cl2/n-hexane, 3:2, as the eluent. Yield 1.16 g, 65%. M.p. 71Ϫ72
°C. EIMS: m/z [ion] (rel. int.%) 356 [M ϩ 2]ϩ (14), 275 [M Ϫ Br]ϩ
3-Bromo-4-(2,4-dibromophenoxy)benzaldehyde (57): This com-
pound was prepared from 3-bromo-4-fluorobenzaldehyde (1.62 g,
8.0 mmol) in DMAC (10 mL), with a reaction time of 2 h. The
silica gel eluent was n-hexane/CH2Cl2, 1:1. Yield 2.70 g, 78% as an
oil. EIMS: m/z [ion] (rel. int.%) 434 [M ϩ 2]ϩ (100), 433 [M Ϫ H
1
(40), 120 [M Ϫ C6H4Br2]ϩ (100). H NMR: see Table 1.
1
ϩ 2]ϩ (34), 246 [M Ϫ 2 BrCO]ϩ (34). H NMR: see Table 1.
3-Chloro-2-(2,4-dibromophenoxy)benzaldehyde (7): This compound
was prepared from 10 (0.79 g, 5.0 mmol) in DMAC (6 mL), with a
reaction time of 3 h. The silica gel eluent was n-hexane/ethyl acetate
7:1. Yield 1.13 g, 58%. M.p. 112Ϫ113.5 °C. EIMS: m/z [ion] (rel.
int.%) 390 [M ϩ 2]ϩ (18), 311 [M Ϫ Br ϩ 2]ϩ (27), 154 [M Ϫ
Preparation of Phenols from Benzaldehydes by Baeyer؊Villiger
Oxidation and Hydrolysis: KH2PO4 (20 equiv.) was added to a solu-
tion of the benzaldehyde (1.7Ϫ8.0 mmol, 1 equiv.) in CH2Cl2
(15Ϫ30 mL). The reaction mixture was cooled to 0 °C, a solution
of TFPA was added dropwise over 0.5 h, and the mixture was
stirred at 0 °C for 0.5Ϫ2 h. The TFPA solution was prepared by
1
C6H4Br2]ϩ (100). H NMR: see Table 1.
5-Bromo-2-(2,4-dibromophenoxy)benzaldehyde (8): This compound
was prepared from 11 (1.02 g, 5.0 mmol) in DMAC (6 mL), with a dropwise addition of trifluoroacetic anhydride (7.5 equiv.) to aque-
reaction time of 1 h. The product was isolated by recrystallization
from MeOH/CH2Cl2, 3:1, and the residue was purified by silica
ous hydrogen peroxide (30%, 1.5 equiv.) in CH2Cl2 (2 mL) at 0 °C,
and the mixture was stirred at 0 °C for 1 h. The reaction mixture
2572
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2566Ϫ2576

Synthesis of Hydroxylated and Methoxylated Polybrominated Diphenyl Ethers
FULL PAPER
1
Table 3. H NMR spectroscopic data for the MeO-PBDEs
Anisole ring
4
2Ј,4Ј-Dibromo ring
Coupling constants
2
3
5
6
3Ј
5Ј
6Ј
MeO
4
3
24
OAr
Br
6.76
Br
7.37[a] 7.30[a] Br
7.76
7.78
7.77
7.74
7.30
7.35
7.26
7.21
6.32
6.68
6.32
6.32
3.85
3.91
3.86
3.77
3J4-H,5-H ϭ 8.8; J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
25[b] OAr
7.36
7.75
7.23
Br
Br
7.11
Br
Br
6.95
3J3-H,4-H ϭ 8.8;, J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.7
3
26
27
OAr
OAr
4J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
Br
3J4-H,5-H ϭ 8.1; J4-H,6-H ϭ 1.5; J5-H,6-H ϭ 8.3;
4J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
3
4
4
28
OAr
6.80
7.06
Br
7.12
7.74
7.29
6.59
3.81
3J3-H,4-H ϭ 8.4; J4-H,6-H ϭ 2.2; J3Ј-H,5Ј-H ϭ 2.4;
3J5Ј-H,6Ј-H ϭ 8.8
4
3
29
30
31
32
33
39
40
41
52
OAr
OAr
OAr
OAr
OAr
OAr
OAr
OAr
6.61
Br
6.92
Cl
Br
7.12
Br
Br
Br
OAr
7.41[a] Br
7.09[a] 7.75
7.23
7.39
7.26
7.26
7.41
7.26
7.23
7.26
7.39
6.32
6.75
6.33
6.31
6.76
6.33
6.30
6.31
6.85
3.77
3.90
3.85
3.84
3.92
3.86
3.77
3.85
3.86
3J4-H,6-H ϭ 2.2; J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4
3
Br
Br
Br
Br
7.50
Br
Br
Br
Br
Cl
7.29
Br
Br
7.79
7.77
7.77
7.80
7.77
7.75
7.78
7.78
4J3-H,5-H ϭ 2.2; J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
3
7.79
7.81
Br
4J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
4J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
3
4J3Ј-H,5Ј-H ϭ 2.5; J5Ј-H,6Ј-H ϭ 8.7
3
3
7.73
Br
Br
Br
Br
Br
4J3Ј-H,5Ј-H ϭ 2.2; J5Ј-H,6Ј-H ϭ 8.8
4J3Ј-H,5Ј-H ϭ 2.2; J5Ј-H,6Ј-H ϭ 8.8
3
4J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
3
3
4
6.36
7.45
4J2-H,4-H ϭ 2.6; J4-H,5-H ϭ 8.7; J3Ј-H,5Ј-H ϭ 2.3;
3J5Ј-H,6Ј-H ϭ 8.6
4
3
53
55
62
Br
OAr
6.52[a] 7.44[a] Br
7.79
7.79
7.75
7.38
7.36
7.28
6.74
6.64
6.51
3.94
3.79
3.81
3J4-H,5-H ϭ 8.9; J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
6.48[a] OAr
Br
OAr
7.79[a] Br
4J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
3
3
4
7.17
Br
6.95
6.85
4J2-H,6-H ϭ 2.9; J5-H,6-H ϭ 9.0; J3Ј-H,5Ј-H ϭ 2.4;
3J5Ј-H,6Ј-H ϭ 8.8
3
63
64
65
Br
Br
Br
Br
Br
OAr
OAr
7.01
Br
7.80
7.40
7.30
7.33
6.73
6.53
6.58
3.89
3.91
3.91
4J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.6
4
3
6.87[a] 6.97[a] 7.77
3J5-H,6-H ϭ 9.1; J3Ј-H,5Ј-H ϭ 2.4; J5Ј-H,6Ј-H ϭ 8.8
7.18[a] OAr
Br
7.14[a] 7.77
4J3Ј-H,5Ј-H ϭ 2.3; J5Ј-H,6Ј-H ϭ 8.7
3
[a]
[b]
Tentative assignment Ϫ chemical shifts may be interchanged. Assignment verified by selective irradiation experiments.
was diluted with brine (15Ϫ25 mL) and aqueous NaHSO3 (20%,
3-Bromo-2-(2,4-dibromophenoxy)phenol (14): This compound was
5Ϫ15 mL) at 0 °C. The phases were separated and the aqueous prepared from 1 (0.74 g, 1.70 mmol) in CH2Cl2 (15 mL), with a
layer was extracted once with an equal volume of CH2Cl2. The
combined organic layers were washed once with an equal volume
of saturated NaHCO3 and water. The crude formate ester was dis-
solved in MeOH (20Ϫ30 mL) containing one drop of concentrated
hydrochloric acid. The solution was stirred for 15 h and then con-
centrated in vacuo. The crude product was purified on a silica gel
column.
reaction time of 2 h. The silica gel eluent was CH2Cl2/n-hexane,
2:1. Yield 0.69 g, 96%. M.p. 98.5Ϫ99.5 °C. EIMS: m/z [ion] (rel.
int.%) 422 [M ϩ 2]ϩ (83), 262 [M Ϫ 2 Br]ϩ (100), 236 [M Ϫ
1
C6H3BrO2 ϩ 2]ϩ (11). H NMR: see Table 2.
3-Bromo-4-(2,4-dibromophenoxy)phenol (58): This compound was
prepared from 57 (2.61 g, 6.0 mmol) in CH2Cl2 (30 mL), with a
reaction time of 1.5 h. The silica gel eluent was CH2Cl2. Yield
2.41 g, 95%. M.p. 88Ϫ89 °C. EIMS: m/z [ion] (rel. int.%) 422 [M
The preparation of 3,5-dibromo-2-(2,4-dibromophenoxy)phenol 16
was carried out at room temperature with aqueous hydrogen per-
oxide (30%, 4.0 equiv.), trifluoroacetic anhydride (20.0 equiv.), and
KH2PO4 (53 equiv.), with a reaction time of 15 h.
1
ϩ 2]ϩ (100), 262 [M Ϫ 2 Br]ϩ (89). H NMR: see Table 2.
5-Bromo-2-(2,4-dibromophenoxy)phenol (15): This compound was
prepared from 8 (1.74 g, 4.0 mmol) in CH2Cl2 (25 mL), with a reac-
tion time of 1.5 h. The silica gel eluent was n-hexane/CH2Cl2, 3:2.
Yield 1.67 g, 99%. M.p. 52Ϫ53.5 °C. EIMS: m/z [ion] (rel. int.%)
3-Chloro-2-methoxyphenol (47): This compound was prepared from
46 (1.36 g, 8.0 mmol) in CH2Cl2 (30 mL), with a reaction time of
1 h. The silica gel eluent was CH2Cl2/n-hexane, 4:1. Yield 1.05 g,
422 [M ϩ 2]ϩ (81), 262 [M Ϫ 2 Br]ϩ (100), 236 [M Ϫ C6H3BrO2
1
1
83%. M.p. 34Ϫ35.5 °C (ref.[43] 32Ϫ33 °C). H NMR: δ ϭ 3.93 (s, ϩ 2]ϩ (14). H NMR: see Table 2.
3
4
3 H, OCH3), 5.74 (br. s, 1 H, OH), 6.87 (dd, JH,H ϭ 7.8, J4-H,6-
3-Chloro-2-(2,4-dibromophenoxy)phenol (13): This compound was
prepared from 7 (0.98 g, 2.5 mmol) in CH2Cl2 (20 mL), with a reac-
tion time of 1.5 h. The silica gel eluent was CH2Cl2/n-hexane, 2:1.
Yield 0.74 g, 78%. M.p. 94Ϫ95 °C. EIMS: m/z [ion] (rel. int.%) 378
3
ϭ 2.0, 1 H, 4-H or 6-H), 6.89 (dd, JH,H ϭ 7.8, 4-H or 6-H),
H
6.94 (t, 1 H, 5-H) ppm. EIMS: m/z [ion] (rel. int.%) 158 [M]ϩ (86),
143 [M Ϫ CH3]ϩ (100), 115 [M Ϫ CH3CO]ϩ (32).
1
2-(2,4-Dibromophenoxy)phenol (12): This compound was prepared
from 6 (1.07 g, 3.0 mmol) in CH2Cl2 (25 mL), with a reaction time
of 1 h. The silica gel eluent was CH2Cl2/n-hexane, 3:2. Yield 1.01 g,
98% as an oil. EIMS: m/z [ion] (rel. int.%) 344 [M ϩ 2]ϩ (53), 184
[M ϩ 2]ϩ (58), 218 [M Ϫ 2 Br]ϩ (100). H NMR: see Table 2.
3,5-Dibromo-2-(2,4-dibromophenoxy)phenol (16): This compound
was prepared from 2 (1.03 g, 2.0 mmol) in CH2Cl2 (20 mL). The
silica gel eluent was CH2Cl2/n-hexane, 5:2. Yield 0.76 g, 76%. M.p.
171Ϫ172 °C, (ref.[23] 171Ϫ173 °C). EIMS: m/z [ion] (rel. int.%) 502
1
[M Ϫ 2 Br]ϩ (100). H NMR: see Table 2.
3-(2,4-Dibromophenoxy)phenol (49): This compound was prepared
[M ϩ 4]ϩ (90), 342 [M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M Ϫ C6H2Br2O2
from 48 (0.71 g, 2.0 mmol) in CH2Cl2 (15 mL), with a reaction time ϩ 2]ϩ (18). H NMR: see Table 2.
1
of 2 h. The silica gel eluent was CH2Cl2. Yield 0.57 g, 83% as an
ortho-Bromination of Phenols: Bromine (1 equiv.) in CH2Cl2 (2 mL)
was added dropwise at Ϫ30 to Ϫ35 °C to tert-butylamine (2 equiv.)
in toluene (25 mL), and the reaction mixture was stirred at this
oil. EIMS: m/z [ion] (rel. int.%) 344 [M ϩ 2]ϩ (21), 184 [M Ϫ 2 Br]ϩ
1
(100). H NMR: see Table 2.
Eur. J. Org. Chem. 2003, 2566Ϫ2576
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2573

˚
G. Marsh, R. Stenutz, A. Bergman
FULL PAPER
temperature for 1 h. The phenoxyphenol (1.2Ϫ2.0 mmol, 1 equiv.) 342 [M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M Ϫ C6H2Br2O2 ϩ 2]ϩ (20). H
1
in CH2Cl2 (5 mL) was added at Ϫ70 °C, and the mixture was
stirred at Ϫ65 to Ϫ60 °C for 4Ϫ6 h. Compound 16 was dissolved
in CH2Cl2 (5 mL) and THF (1 mL). The reaction was quenched at
Ϫ70 °C by dropwise addition of water (1 mL) in ethanol (9 mL),
while a stream of sulfur dioxide was simultaneously passed through
the reaction mixture. After the mixture had been stirred at Ϫ70 °C
for 10 min (during which time the mixture changed from pale yel-
low to colorless and a white solid) it was allowed to warm to room
temperature. CH2Cl2 (50 mL) and water (50 mL) were added, and
the organic layer was separated and washed with water (2 ϫ
50 mL). The crude product was purified by silica gel chromatogra-
phy.
NMR: see Table 2.
4,6-Dibromo-3-chloro-2-(2,4-dibromophenoxy)phenol (21): This
compound was prepared from 13 (0.61 g, 1.6 mmol). The silica gel
eluent was n-hexane/CH2Cl2, 1:1. Yield 0.83 g, 97%. M.p. 149Ϫ150
°C. EIMS: m/z [ion] (rel. int.%) 536 [M ϩ 4]ϩ (77), 375 [M Ϫ
2 Br ϩ 2]ϩ (100), 236 [M Ϫ C6HBr2ClO2 ϩ 2]ϩ (40). 1H NMR:
see Table 2.
3,4,6-Tribromo-2-(2,4-dibromophenoxy)phenol (22): This compound
was prepared from 14 (0.51 g, 1.2 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 1:1. Yield 0.67 g, 96%. M.p. 126Ϫ127 °C. EIMS:
m/z [ion] (rel. int.%) 580 [M ϩ 4]ϩ (81), 420 [M Ϫ 2 Br ϩ 2]ϩ (100),
236 [M Ϫ C6HBr3O2 ϩ 2]ϩ (40). H NMR: see Table 2.
1
2,6-Dibromo-3-(2,4-dibromophenoxy)phenol (51) and 6-Bromo-3-
(2,4-dibromophenoxy)phenol (50): These compounds were prepared
by the di-ortho-bromination of 49 (0.57 g, 1.65 mmol). The reaction
time was 6 h and the silica gel eluent was n-hexane/CH2Cl2, 1:1.
51: Yield 0.41 g, 50%. M.p. 95Ϫ96.5 °C. EIMS: m/z [ion] (rel.
4,5,6-Tribromo-2-(2,4-dibromophenoxy)phenol (23): This compound
was prepared from 15 (1.65 g, 3.9 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 1:1. Yield 2.20 g, 97%. M.p. 140Ϫ141 °C (ref.[20]
138Ϫ140 °C). EIMS: m/z [ion] (rel. int.%) 580 [M ϩ 4]ϩ (77), 420
[M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M Ϫ C6HBr3O2 ϩ 2]ϩ (36). 1H NMR:
see Table 2.
1
int.%) 502 [M ϩ 4]ϩ (37), 342 [M Ϫ 2 Br ϩ 2]ϩ (100). H NMR:
see Table 3. 50: Yield 0.20 g, 29% as an oil. EIMS: m/z [ion] (rel.
int.%) 422 [M ϩ 2]ϩ (36), 262 [M Ϫ 2 Br]ϩ (100). 1H NMR: see
Table 2.
Monobromination of 3-Bromo-4-(2,4-dibromophenoxy)phenol: Bro-
mine (5.6 mmol, 0.287 mL) in acetic acid (10 mL) was added drop-
wise, over 30 min at room temperature, to a solution of 58 (2.37 g,
5.6 mmol) in acetic acid (20 mL). After stirring for an additional
3 h, the reaction mixture was treated with water (30 mL) and ex-
tracted with CH2Cl2 (3 ϫ 50 mL). The combined organic layers
were washed with aqueous NaHSO3 (5%, 150 mL) and water (2 ϫ
150 mL). Purification of the crude products on a silica gel column,
eluting with CH2Cl2/n-hexane, 2:1, gave the starting compound 58
(0.12 g, 5%), the pentabrominated OH-PBDE 61, and the two ex-
pected tetrabrominated OH-PBDEs as a mixture (2.25 g, 80%). The
mixture of 59 and 60 was methylated as described below and sepa-
rated on a silica gel column, eluted with n-hexane/ethyl acetate 6:1.
3,6-Dibromo-2-(2,4-dibromophenoxy)phenol (17): This compound
was prepared from 14 (0.51 g, 1.2 mmol). The reaction time was
4 h and the silica gel eluent was CH2Cl2/n-hexane, 2:1. Yield 0.48 g,
80%. M.p. 93.5Ϫ95 °C. EIMS: m/z [ion] (rel. int.%) 502 [M ϩ 4]ϩ
(74), 342 [M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M Ϫ C6H2Br2O2 ϩ 2]ϩ (20).
1H NMR: see Table 2.
5,6-Dibromo-2-(2,4-dibromophenoxy)phenol (18): This compound
was prepared from 15 (0.85 g, 2.0 mmol). The reaction time was
4 h and the silica gel eluent was n-hexane/CH2Cl2, 1:1. Yield 0.85 g,
85%. M.p. 108Ϫ109.5 °C. EIMS: m/z [ion] (rel. int.%) 502 [M ϩ
4]ϩ (88), 342 [M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M Ϫ C6H2Br2O2 ϩ 2]ϩ
1
2,3,6-Tribromo-4-(2,4-dibromophenoxy)phenol (61): Yield 0.33 g,
10%. M.p. 95Ϫ96.5 °C. EIMS: m/z [ion] (rel. int.%) 580 [M ϩ 4]ϩ
(24). H NMR: see Table 2.
3,5,6-Tribromo-2-(2,4-dibromophenoxy)phenol (19): This compound
was prepared from 16 (0.70 g, 1.4 mmol). The reaction time was
4 h and the silica gel eluent was CH2Cl2/n-hexane, 5:2. Yield 0.60 g,
74%. M.p. 114.5Ϫ115.5 °C, (ref.[1] 113Ϫ114 °C). EIMS: m/z [ion]
(rel. int.%) 580 [M ϩ 4]ϩ (78), 420 [M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M
(68), 420 [M Ϫ 2 Br ϩ 2]ϩ (100). H NMR: see Table 2.
1
2,3-Dibromo-4-(2,4-dibromophenoxy)anisole (64): Yield (two steps
from 58) 0.38 g, 13%. M.p. 148Ϫ149 °C. EIMS: m/z [ion] (rel.
int.%) 516 [M ϩ 4]ϩ (100), 501 [M Ϫ CH3 ϩ 4]ϩ (21), 356 [M Ϫ
2 Br ϩ 2]ϩ (32), 341 [M Ϫ 2 BrCH3 ϩ 2]ϩ (21), 313 [M Ϫ
1
Ϫ C6HBr3O2 ϩ 2]ϩ (36). H NMR: see Table 2.
2 BrCH3CO ϩ 2]ϩ (20). H NMR: see Table 3.
1
ortho/para-Bromination of Phenols: BTMA-Br3 (2.2 equiv.) was ad-
ded in small portions over time (5 h), at room temperature, to a
mixture of the phenol (1.2Ϫ3.9 mmol, 1 equiv.) and CaCO3 (3
equiv.) in CH2Cl2 (25Ϫ50 mL) and MeOH (10Ϫ20 mL) (in a ratio
of 5:2). After stirring for an additional 1 h, the reaction mixture
was filtered and treated with aqueous NaHSO3 (5%, 40 mL) while
being stirred. The organic layer was separated and the water phase
was extracted with CH2Cl2 (30 mL). The combined organic phase
was washed with water (2 ϫ 50 mL). The crude product was puri-
fied by silica gel chromatography.
2,5-Dibromo-4-(2,4-dibromophenoxy)anisole (65): Yield (two steps
from 58) 1.86 g, 64%. M.p. 111Ϫ112 °C. EIMS: m/z [ion] (rel.
int.%) 516 [M ϩ 4]ϩ (100), 501 [M Ϫ CH3 ϩ 4]ϩ (18), 356 [M Ϫ
2 Br ϩ 2]ϩ (25), 341 [M Ϫ 2 BrCH3 ϩ 2]ϩ (22), 313 [M Ϫ
1
2 BrCH3CO ϩ 2]ϩ (22). H NMR: see Table 3.
General Procedure for Methylation of Phenols: Phenol
(0.40Ϫ8.0 mmol, 1.0 equiv.), NaOH (3.0 equiv.), and tetrabutylam-
monium hydroxide (2.0 equiv.) were distributed between equal vol-
umes of CH2Cl2 (5Ϫ30 mL) and water (5Ϫ30 mL). Iodomethane
(5.0 equiv.) was added, and the reaction mixture was stirred at
room temperature for 5 h. The layers were separated and the water
phase was extracted once with one volume of CH2Cl2. The crude
product was purified by silica gel chromatography.
2,4-Dibromo-5-chloro-6-methoxyphenol (35): This compound was
prepared from 47 (0.48 g, 3.0 mmol). The silica gel eluent was n-
1
hexane/ethyl acetate, 3:1. Yield 0.83 g, 87%. M.p. 105Ϫ106 °C. H
NMR: δ ϭ 3.94 (s, 3 H, OCH3), 5.95 (br. s, 1 H, OH), 7.56 (s, 1
H, 5-H) ppm. EIMS: m/z [ion] (rel. int.%) 316 [M ϩ 2]ϩ (100), 301
3-Chloro-2-methoxybenzaldehyde (46): This compound was pre-
pared from 45 (1.25 g, 8.0 mmol). The silica gel eluent was CH2Cl2/
1
[M Ϫ CH3 ϩ 2]ϩ (65), 273 [M Ϫ CH3CO ϩ 2]ϩ (27). H NMR:
see Table 2.
1
n-hexane, 5:1. Yield 1.32 g, 97%. M.p. 29.5Ϫ31 °C. H NMR: δ ϭ
3
3
4
4,6-Dibromo-2-(2,4-dibromophenoxy)phenol (20): This compound
was prepared from 12 (0.96 g, 2.8 mmol). The silica gel eluent was
n-hexane/ethyl acetate 6:1. Yield 1.31 g, 93%. M.p. 88Ϫ89.5 °C
7.19 (dd, J4-H,5-H ϭ 7.9, J5-H,6-H ϭ 7.7, 1 H, 5-H), 7.64 (dd, J4-
ϭ 1.6, 1 H, 4-H), 7.76 (dd, 1 H, 6-H), 10.38 (s, 1 H, CHO)
H,6-H
ppm. EIMS: m/z [ion] (rel. int.%) 170 [M]ϩ (95), 169 [M Ϫ H]ϩ
(ref.[23] 90Ϫ91 °C). EIMS: m/z [ion] (rel. int.%) 502 [M ϩ 4]ϩ (62), (35), 155 [M Ϫ CH3]ϩ (64), 152 [M Ϫ CH4]ϩ (100).
2574
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2566Ϫ2576

Synthesis of Hydroxylated and Methoxylated Polybrominated Diphenyl Ethers
FULL PAPER
3-Bromo-2-(2,4-dibromophenoxy)anisole (27): This compound was
prepared from 14 (0.34 g, 0.8 mmol). The silica gel eluent was n-
hexane/CH2Cl2, 2:1. Yield 0.345 g, 99% as an oil. M.p. ref.[23]
78.5Ϫ79.5 °C. EIMS: m/z [ion] (rel. int.%) 436 [M ϩ 2]ϩ (100), 342
[M Ϫ BrCH3 ϩ 2]ϩ (48), 276 [M Ϫ 2 Br]ϩ (36), 261 [M Ϫ
2 BrCH3]ϩ (10), 233 [M Ϫ 2 BrCH3CO]ϩ (20). 1H NMR: see
Table 3.
2,3,6-Tribromo-4-(2,4-dibromophenoxy)anisole (63): This com-
pound was prepared from 61 (0.145 g, 0.25 mmol). The silica gel
eluent was n-hexane/CH2Cl2, 2:1. Yield 0.147 g, 99%. M.p.
104Ϫ105 °C. EIMS: m/z [ion] (rel. int.%) 594 [M ϩ 4]ϩ (100), 579
[M Ϫ CH3 ϩ 4]ϩ (39), 434 [M Ϫ 2 Br ϩ 2]ϩ (24), 419 [M Ϫ
1
2 BrCH3 ϩ 2]ϩ (25), 391 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (21). H NMR:
see Table 3.
3-Bromo-4-(2,4-dibromophenoxy)anisole (62): This compound was
prepared from 58 (0.423 g, 1.0 mmol). The silica gel eluent was n-
hexane/CH2Cl2, 2:1.Yield 0.433 g, 99%. M.p. 57Ϫ58 °C. EIMS: m/
z [ion] (rel. int.%) 436 [M ϩ 2]ϩ (100), 421 [M Ϫ CH3 ϩ 2]ϩ (11),
276 [M Ϫ 2 Br]ϩ (29), 261 [M Ϫ 2 BrCH3]ϩ (17), 233 [M Ϫ
3,4,6-Tribromo-2-(2,4-dibromophenoxy)anisole (32): This com-
pound was prepared from 22 (0.29 g, 0.50 mmol). The silica gel
eluent was n-hexane/CH2Cl2, 3:1. Yield 0.29 g, 98%. M.p. 78Ϫ79.5
°C. EIMS: m/z [ion] (rel. int.%) 594 [M ϩ 4]ϩ (100), 500 [M Ϫ
BrCH3 ϩ 4]ϩ (60), 434 [M Ϫ 2 Br ϩ 2]ϩ (63), 419 [M Ϫ 2 BrCH3 ϩ
2]ϩ (13), 391 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (21). 1H NMR: see Table 3.
1
2 BrCH3CO]ϩ (18). H NMR: see Table 3.
5-Bromo-2-(2,4-dibromophenoxy)anisole (28): This compound was
prepared from 15 (0.423 g, 1.0 mmol). The silica gel eluent was n-
hexane/CH2Cl2, 2:1. Yield 0.433 g, 99% as an oil. EIMS: m/z [ion]
(rel. int.%) 436 [M ϩ 2]ϩ (100), 342 [M Ϫ BrCH3 ϩ 2]ϩ (58), 276
3,5,6-Tribromo-2-(2,4-dibromophenoxy)anisole (26): This com-
pound was prepared from 19 (0.25 g, 0.43 mmol). The silica gel
eluent was n-hexane/CH2Cl2, 4:1.Yield 0.255 g, 100%. M.p.
112Ϫ113 °C. EIMS: m/z [ion] (rel. int.%) 594 [M ϩ 4]ϩ (100), 500
[M Ϫ BrCH3 ϩ 4]ϩ (52), 434 [M Ϫ 2 Br ϩ 2]ϩ (35), 419 [M Ϫ
[M
Ϫ
2 Br]ϩ (20), 261 [M
Ϫ
2 BrCH3]ϩ (8), 233 [M
Ϫ
1
2 BrCH3CO]ϩ (16). H NMR: see Table 3.
1
2 BrCH3 ϩ 2]ϩ (6), 391 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (16). H NMR:
6-Bromo-3-(2,4-dibromophenoxy)anisole (52): This compound was
prepared from 50 (0.101 g, 0.24 mmol). The silica gel eluent was n-
hexane/CH2Cl2, 2:1. Yield 0.103 g, 98% as an oil. EIMS: m/z [ion]
(rel. int.%) 436 [M ϩ 2]ϩ (47), 276 [M Ϫ 2 Br]ϩ (100), 261 [M Ϫ
2 BrCH3]ϩ (36), 233 [M Ϫ 2 BrCH3CO]ϩ (17). 1H NMR: see
Table 3.
see Table 3.
4,5,6-Tribromo-2-(2,4-dibromophenoxy)anisole (33): This com-
pound was prepared from 23 (1.16 g, 2.0 mmol). The silica gel elu-
ent was n-hexane/CH2Cl2, 3:1. Yield 1.17 g, 98%. M.p. 87Ϫ88 °C.
EIMS: m/z [ion] (rel. int.%) 594 [M ϩ 4]ϩ (100), 500 [M Ϫ BrCH3
ϩ 4]ϩ (77), 434 [M Ϫ 2 Br ϩ 2]ϩ (34), 419 [M Ϫ 2 BrCH3 ϩ 2]ϩ
(8), 391 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (15). H NMR: see Table 3.
3,5-Dibromo-2-(2,4-dibromophenoxy)anisole (29): This compound
was prepared from 16 (0.50 g, 1.0 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 3:1. Yield 0.505 g, 98%. 1H NMR: see Table 3.
For m.p. and EIMS, see 29 above.
1
General Demethylation Procedure: Boron tribromide (10 equiv.) was
added to a solution of the MeO-PBDEs (0.625Ϫ1.0 mmol, 1 equiv.)
in CH2Cl2 (15 mL), and the mixture was heated at 50 °C until all
starting material had reacted (5Ϫ48 h). Water (15 mL) was care-
fully added at 0 °C, and the layers were separated and the water
phase was extracted once with one volume of CH2Cl2. The crude
product was purified by silica gel chromatography.
3,6-Dibromo-2-(2,4-dibromophenoxy)anisole (24): This compound
was prepared from 17 (0.20 g, 0.40 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 3:1. Yield 0.20 g, 97%. M.p. 112Ϫ113 °C. EIMS:
m/z [ion] (rel. int.%) 516 [M ϩ 4]ϩ (100), 420 [M Ϫ BrCH3 ϩ 2]ϩ
(54), 356 [M Ϫ 2 Br ϩ 2]ϩ (59), 341 [M Ϫ 2 BrCH3 ϩ 2]ϩ (11),
1
313 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (26). H NMR: see Table 3.
2,3-Dibromo-4-(2,4-dibromophenoxy)phenol (59): This compound
was prepared from 64 (0.206 g, 0.40 mmol). The silica gel eluent
was CH2Cl2/n-hexane, 2:1.Yield 0.199 g, 99%. M.p. 82.5Ϫ83.5 °C.
EIMS: m/z [ion] (rel. int.%) 502 [M ϩ 4]ϩ (89), 342 [M Ϫ 2 Br ϩ
4,6-Dibromo-2-(2,4-dibromophenoxy)anisole (30): This compound
was prepared from 20 (0.75 g, 1.5 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 2:1. Yield 0.74 g, 96% as an oil. EIMS: m/z [ion]
(rel. int.%) 516 [M ϩ 4]ϩ (100), 420 [M Ϫ BrCH3 ϩ 2]ϩ (75), 356
[M Ϫ 2 Br ϩ 2]ϩ (52), 341 [M Ϫ 2 BrCH3 ϩ 2]ϩ (11), 313 [M Ϫ
1
2]ϩ (100). H NMR: see Table 2.
3,5-Dibromo-2-(2,4-dibromophenoxy)phenol (16): This compound
was prepared from 29 (0.32 g, 0.625 mmol). The silica gel eluent
was CH2Cl2/n-hexane, 5:2. Yield 0.30 g, 96%. 1H NMR: see
Table 3. For m.p. and EIMS, see 16 above.
1
2 BrCH3CO ϩ 2]ϩ (25). H NMR: see Table 3.
5,6-Dibromo-2-(2,4-dibromophenoxy)anisole (25): This compound
was prepared from 18 (0.50 g, 1.0 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 3:1. Yield 0.505 g, 98% as an oil. EIMS: m/z [ion]
(rel. int.%) 516 [M ϩ 4]ϩ (100), 420 [M Ϫ BrCH3 ϩ 2]ϩ (63), 356
[M Ϫ 2 Br ϩ 2]ϩ (29), 341 [M Ϫ 2 BrCH3 ϩ 2]ϩ (9), 313 [M Ϫ
4,6-Dibromo-3-(2,4-dibromophenoxy)phenol (56): This compound
was prepared from 55 (0.20 g, 0.39 mmol). The reaction time was
5 h and the silica gel eluent was CH2Cl2/n-hexane, 3:2. Yield
0.194 g, 99%. M.p. 82.5Ϫ84 °C. EIMS: m/z [ion] (rel. int.%) 502
1
2 BrCH3CO ϩ 2]ϩ (20). H NMR: see Table 3.
[M ϩ 4]ϩ (51), 342 [M Ϫ 2 Br]ϩ (100). H NMR: see Table 2.
1
2,6-Dibromo-3-(2,4-dibromophenoxy)anisole (53): This compound
was prepared from 51 (0.20 g, 0.40 mmol). The silica gel eluent was
n-hexane/CH2Cl2, 3:2. Yield 0.205 g, 99% as an oil. EIMS: m/z [ion]
(rel. int.%) 516 [M ϩ 4]ϩ (70), 356 [M Ϫ 2 Br ϩ 2]ϩ (100), 341 [M
Ϫ 2 BrCH3 ϩ 2]ϩ (64), 313 [M Ϫ 2 BrCH3CO ϩ 2]ϩ (24). 1H
NMR: see Table 3.
2,5-Dibromo-4-(2,4-dibromophenoxy)phenol (60): This compound
was prepared from 65 (1.03 g, 2.0 mmol). The silica gel eluent was
CH2Cl2/n-hexane, 2:1.Yield 0.987 g, 98%. M.p. 90Ϫ91 °C. EIMS:
m/z [ion] (rel. int.%) 502 [M ϩ 4]ϩ (100), 342 [M Ϫ 2 Br ϩ 2]ϩ
1
(98). H NMR: see Table 2.
4,6-Dibromo-3-chloro-2-(2,4-dibromophenoxy)anisole (31): This
compound was prepared from 21 (0.40 g, 0.75 mmol). The silica 3,5-Dibromo-6-chloro-2-(2,4-dibromophenoxy)phenol (42): This
gel eluent was n-hexane/CH2Cl2, 2:1. Yield 0.405 g, 98%. M.p.
compound was prepared from 39 (0.41 g, 0.75 mmol). The reaction
time was 36 h and the silica gel eluent was CH2Cl2/n-hexane, 2:1.
101Ϫ102 °C. EIMS: m/z [ion] (rel. int.%) 550 [M ϩ 4]ϩ (100), 456
[M Ϫ BrCH3 ϩ 4]ϩ (65), 434 [M Ϫ BrCl ϩ 2]ϩ (14), 390 [M Ϫ Yield 0.39 mg, 97%. M.p. 97Ϫ98.5 °C. EIMS: m/z [ion] (rel. int.%)
2 Br ϩ 2]ϩ (30), 375 [M Ϫ 2 BrCH3 ϩ 2]ϩ (11), 347 [M Ϫ 536 [M ϩ 4]ϩ (72), 375 [M Ϫ 2 Br ϩ 2]ϩ (100), 236 [M Ϫ
2 BrCH3CO ϩ 2]ϩ (19). H NMR: see Table 3.
C6HBr2ClO2 ϩ 2]ϩ (28). H NMR: see Table 2.
1
1
Eur. J. Org. Chem. 2003, 2566Ϫ2576
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2575

˚
G. Marsh, R. Stenutz, A. Bergman
FULL PAPER
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3,4,5,6-Tetrabromo-2-(2,4-dibromophenoxy)phenol (44): This com-
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Received February 7, 2003
2576
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2566Ϫ2576