Total synthesis of the biologically active, naturally occurring 3,4-dibromo-5-[2-bromo-3,4-dihydroxy-6-(methoxymethyl)benzyl]benzene-1,2-diol and regioselective O-demethylation of aryl methyl ethers

Article abstract of DOI:10.1002/hlca.200900300

3,4-Dibromo-5-[2-bromo-3,4-dihydroxy-6-(methoxymethyl)benzyl]benzene-1, 2-diol (2), a natural product, has been synthesized for the first time starting from (3-bromo-4,5-dimethoxyphenyl)methanol (5) in five steps and with an overall yield of 34%. The reaction of some methoxymethyl-substituted aryl methyl ethers with BBr₃, followed by the addition of MeOH, afforded the corresponding methoxymethyl-substituted arylphenols in high yields.

Full text of DOI:10.1002/hlca.200900300

Helvetica Chimica Acta – Vol. 93 (2010)
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Total Synthesis of the Biologically Active, Naturally Occurring 3,4-Dibromo-
5-[2-bromo-3,4-dihydroxy-6-(methoxymethyl)benzyl]benzene-1,2-diol and
Regioselective O-Demethylation of Aryl Methyl Ethers
by Yusuf Akbaba, Halis Tꢀrker Balaydın, Sꢀleyman Gçksu*, Ertan S¸ahin, and Abdullah Menzek*
Department of Chemistry, Faculty of Science, Ataturk University, TR-25240 Erzurum
(phone: 904422314389; fax: 904422360948; e-mail: sgoksu@atauni.edu.tr)
(phone: 904422314423; fax: 904422360948; e-mail: amenzek@atauni.edu.tr)
3,4-Dibromo-5-[2-bromo-3,4-dihydroxy-6-(methoxymethyl)benzyl]benzene-1,2-diol (2), a natural
product, has been synthesized for the first time starting from (3-bromo-4,5-dimethoxyphenyl)methanol
(5) in five steps and with an overall yield of 34%. The reaction of some methoxymethyl-substituted aryl
methyl ethers with BBr3, followed by the addition of MeOH, afforded the corresponding methoxy-
methyl-substituted arylphenols in high yields.
Introduction. – Marine life is one of the most important sources of biologically
active natural products [1]. Halogenated metabolites with significant medicinal value
are abundantly found in marine plants and animals [2]. Bromophenols, frequently
isolated from red algae of the family Rhodomelaceae, are prominent biologically active
compounds [2a – c][3]. The diarylmethane-type bromophenols 5,5’-methylenebis(3,4-
dibromobenzene-1,2-diol) (1) and 3,4-dibromo-5-[2-bromo-3,4-dihydroxy-6-(methoxy-
methyl)benzyl]benzene-1,2-diol (2), were first isolated by Kurata and Amiya [4].
Recently, both of these compounds have been obtained from different sources [5 – 10].
Isolation of the title compound 2 was also reported by Xu et al. and Suzuki et al. [11].
Bromophenols, particularly 1 and 2, exhibit enzyme inhibition [5], cytotoxicity [6], as
well as feeding deterrent [7], microbial [8][9], and fungicidal [12] activities. On the
other hand, 3,4,6-tribromo-5-(2,5-dibromo-3,4-dihydroxybenzyl)benzene-1,2-diol (3)
and 5,5’-methylenebis(3,4,6-tribromobenzene-1,2-diol) (4) show aldose reductase
inhibitory activity [13]. Furthermore, it is known that 4 exhibits antioxidant activity
[14].
Here, we report the first total and convenient synthesis of naturally occurring
benzenediol 2 starting from (3-bromo-4,5-dimethoxyphenyl)methanol (5) and (2,3-
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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dibromo-4,5-dimethoxyphenyl)methanol (6) in five steps. We also investigated the
regioselective O-demethylation of aryl methyl ethers containing a benzyl methyl ether
moiety.
Results and Discussion. – (3-Bromo-4,5-dimethoxyphenyl)methanol (5) [15] and
(2,3-dibromo-4,5-dimethoxyphenyl)methanol (6) [16] were synthesized according to
the procedures described in the literature. For the synthesis of benzyl bromide 7, 5 was
reacted with PBr3 in the presence of Et3N at 0 – 258. One of the most critical steps in the
synthesis of 2 was the alkylation of compound 7 with alcohol 6. Even though the
alkylation or acylation of aromatic compounds with alcohols and carboxylic acids,
respectively, in the presence of polyacids is well described in the literature [17], the
reaction of 6 with 7 might fail by leading to polymerization because of the benzyl
bromide 7. Furthermore, alcohol 6 could have reacted with 7 at either C(2) or C(6).
Fortunately, the reaction of 6 with 7 in the presence of polyphosphoric acid took place
at C(6) to give 8 regioselectively in moderate yield (53%; Scheme 1).
Scheme 1
i) PBr3/ Et3N, CH2Cl2, 0 – 258, 6 h; 84%. ii) H3PO4/P2O5 (polyphosphoric acid, PPA), then compound 7,
808, 30 min; 53%. iii) H2O, dioxane, 1108, 3 d; 95%. iv) NaH/Me2SO4, THF, 0 – 258, 24 h; 97%. v) BBr3,
CH2Cl2, 0 – 258, 24 h, then MeOH, 0 – 608; 82%. vi) BBr3, CH2Cl2, 0 – 258, 24 h, and then H2O, 08; 90%.
1H- and 13C-NMR analysis of 8 did not allow determination of its exact structure.
Therefore, it was established by X-ray diffraction analysis. The structure and
numbering scheme of 8 are illustrated in Fig. 1, and the packing in the crystal is
shown in Fig. 2.

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Fig. 1. Molecular structure of compound 8 showing the atom-numbering scheme. Thermal ellipsoids are
drawn at the 40% probability level.
Fig. 2. Packing diagram for 8, viewed down the a-axis.
The hydrolysis of 8 in dioxane at 1108 gave the corresponding benzyl alcohol 9 in
high yield. The reaction of 9 with NaH, followed by methylation with Me2SO4 at 0 – 258,
yielded the benzyl methyl ether 10 (Scheme 1).
Deprotection of functional groups is often used in organic synthesis, e.g., cleavage
of ethers remains an integral functional group transformation, as it is important for the
synthesis of natural products, pharmaceuticals, and fine chemicals. Although the
procedures for the cleavage of alkyl aryl ethers with HBr [18], BBr3 [19] or with other
methods [20] are well-known, regioselective O-demethylation of methoxymethyl-
substituted aryl methyl ethers remains unknown. Compound 10 contains a MeOCH2
and four MeO groups as substituents. Demethylation of 10 with HBr or other cleaving
reagents (such as HI, AlCl3, BBr3, BCl3) was expected to lead to the ether cleavage at
the benzylic position. Hence, demethylation of the methyl phenyl ether groups of 10
without cleavage of benzyl methyl ether was the most crucial step of the synthesis. For

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this purpose, compound 10 was treated with BBr3 at 0 – 258 under N2 for 24 h. After the
reaction was completed, quenching of excess BBr3 with MeOH at 0 – 608 afforded the
O-demethylation of the methyl phenyl ethers in a one-pot reaction under mild
1
conditions to give the natural compound 2 (Scheme 1). H- and 13C-NMR analysis
showed that no benzyl bromide was formed under these reaction conditions.
To gain more insight into the reaction course, treatment of 10 with BBr3 was
followed by direct addition of H2O to deactivate BBr3, without addition of MeOH,
and the extraction of the organic layer with AcOEt gave the corresponding
bromomethyl-benzenediol 11. This result indicated that the reaction did not pro-
ceed regioselectively. Indeed, the benzyl methyl ether part of compound 10 was also
cleaved, and then, addition of MeOH to the reaction mixture led to compound 2
(Scheme 1).
Although the reaction does not proceed as a regioselective O-demethylation, the
method will be useful for the synthesis of this type of compounds. Therefore, we
focused on the synthesis of some other MeOCH2-substituted aryl methyl ethers, and
their reactions with BBr3 were investigated under the same conditions as those
described above. For this purpose, 3,5-dimethoxybenzaldehyde (12) was brominated
with Br2 in CH2Cl2 at room temperature for 24 h to give the corresponding
dibrominated aldehyde 13 [21]. Reduction of 13 with NaBH4 in MeOH/THF gave
benzyl alcohol 14. The synthesis of 15 was performed according to the procedure
described in [22]. Reaction of alcohols 6, 14, and 15 with Me2SO4 in the presence of
NaH gave benzyl methyl ethers 16 [23], 17, and 18 [22], respectively, in high yields (96,
96, and 94%, resp.). O-Demethylation of 16, 17, and 18 with BBr3 in CH2Cl2 at 0 – 258
under N2, followed by addition of MeOH for deactivation of excess BBr3 at 0 – 608,
afforded MeOCH2-substituted benzene-diols 19 [24], 20, and 21 [25], respectively, in
high yields in a one-pot reaction (Scheme 2).
Scheme 2
i) Br2, CH2Cl2, 258; 92%. ii) NaBH4, THF/MeOH, 258, 24 h, then H2O; 95%. iii) NaH/Me2SO4, THF,
0 – 258, 24 h, then H2O. iv) BBr3, CH2Cl2, 0 – 258, 24 h, then MeOH, 0 – 608.

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Conclusions. – In summary, we have achieved the first and convenient synthesis of
the naturally occurring bromophenol 2 starting from (3-bromo-4,5-dimethoxyphenyl)-
methanol (5) and (2,3-dibromo-4,5-dimethoxyphenyl)methanol (6) in five steps with a
yield of 34%.
Furthermore, we developed a method for a ꢂpseudo-selectiveꢃ O-demethylation of
methoxymethyl-substituted aryl methyl ethers. This method is the first one-pot
synthesis of MeOCH2-substituted benzene-diols. The effectiveness of the methodology
was shown by the preparation of 3,4-dibromo-5-(methoxymethyl)benzene-1,2-diol
(19), 4,6-dibromo-5-(methoxymethyl)benzene-1,3-diol (20), and 3,4,6-tribromo-5-
(methoxymethyl)benzene-1,2-diol (21).
The authors are indebted to the Scientific and Technological Research Council of Turkey
˙
(TꢀBITAK, Grant No: TBAG-107T/348) and Atatꢁrk University for their financial support of this work.
Experimental Part
General. All chemicals and solvents are commercially available and were used after distillation or
treatment with drying agents. Column chromatography (CC): silica gel (SiO2, 60 mesh; Merck). Prep.
thick-layer chromatography (PLC): 1 mm of SiO2 60 PF (Merck) on glass plates. M.p.: cap. melting-point
apparatus (Thomas-Hoover); uncorrected. IR Spectra: solns. in 0.1-mm cells; Perkin-Elmer spectro-
photometer; in cmꢀ1. 1H- and 13C- NMR spectra: 200 (50) and 400 (100)-MHz Varian spectrometer; d in
ppm, J in Hz; Me4Si as the internal standard. ESI-MS: Bruker microTOF-Q. Elemental analyses: Leco
CHNS-932 apparatus.
1-Bromo-5-(bromomethyl)-2,3-dimethoxybenzene (7). To a stirred soln. of (3-bromo-4,5-dimethoxy-
phenyl)methanol (5; 13.0 g, 52.6 mmol) in CH2Cl2 (70 ml) was added Et3N (5.8 g, 57.3 mmol) and a soln.
of PBr3 (15.5 g, 57.3 mmol) in CH2Cl2 (20 ml) dropwise at 08. After the addition was complete, the
mixture was stirred at the same temp. for 30 min. The mixture was warmed to r.t. and stirred for 6 h. After
the evaporation of the solvent, ice (20 g) and HCl (1m, 20 ml) were added to the residue. Org. phase was
extracted with AcOEt (2 ꢁ 50 ml). Drying of org. phase (Na2SO4) and evaporation of the solvent gave 7
(13.7 g, 84%). White solid. M.p. 91 – 938. IR (CH2Cl2): 2937, 2829, 1596, 1568, 1489, 1463, 1428, 1413,
1310, 1277, 1238, 1217, 1144, 1047, 1000. 1H-NMR (400 MHz, CDCl3): 7.16 (d, 4J ¼ 2.02, 1 arom. H); 6.88
4
(d, J ¼ 2.02, 1 arom. H); 4.40 (s, CH2); 3.87 (s, MeO); 3.85 (s, MeO). 13C-NMR (100 MHz, CDCl3):
153.95 (2 C); 134.90 (C); 125.42 (CH); 117.76 (C); 112.64 (CH); 60.84 (MeO); 56.36 (MeO); 32.77
(CH2). Anal. calc. for C9H10Br2O2: C 34.87, H 3.25; found: C 34.89, H 3.18.
2,3-Dibromo-1-[2-bromo-6-(bromomethyl)-3,4-dimethoxybenzyl]-4,5-dimethoxybenzene (8). Poly-
phosphoric acid (PPA), prepared from conc. H3PO4 (5.1 ml) and P2O5 (15.71 g), was heated to 808 in a
beaker (250 ml). To this mixture were added 6 (5.00 g, 15.3 mmol) and 7 (4.76 g, 15.3 mmol). The
mixture was stirred with a glass stick at 808 for 30 min. The mixture was carefully poured onto 50 ml of
ice/water. The org. phase was extracted with AcOEt (2 ꢁ 50 ml). The combined org. layers were dried
(Na2SO4), and the solvent was evaporated. The resulting residue was purified by CC (SiO2 (100 g);
hexane/AcOEt 85 :15) to afford 8 (5.12 g, 53% yield). Yellow needles. M.p. 149 – 1518 (AcOEt/hexane).
IR (CH2Cl2): 2937, 1594, 1549, 1485, 1464, 1422, 1372, 1318, 1283, 1212, 1192, 1162, 1121, 1100, 1039, 1006,
988. 1H-NMR (400 MHz, CDCl3): 6.95 (s, 1 arom. H); 6.16 (s, 1 arom. H); 4.35 (s, CH2); 4.32 (s, CH2);
3.92 (s, MeO); 3.88 (s, MeO); 3.81 (s, MeO); 3.57 (s, MeO). 13C-NMR (100 MHz, CDCl3): 152.69 (C);
152.65 (C); 147.44 (C); 146.44 (C); 135.71 (C); 133.79 (C); 130.79 (C); 123.13 (C); 122.13 (C); 117.79 (C);
113.97 (CH); 112.27 (CH); 60.80 (MeO); 60.74 (MeO); 56.37 (MeO); 56.33 (MeO); 39.93 (CH2); 32.03
(CH2). Anal. calc. for C18H18Br4O4: C 34.99, H 2.94; found: C 35.01, H 2.90.
[3-Bromo-2-(2,3-dibromo-4,5-dimethoxybenzyl)-4,5-dimethoxyphenyl]methanol (9). To a stirred
soln. of 8 (1.0 g, 1.6 mmol) in dioxane (30 ml) was added H2O (20 ml), and the mixture was stirred at
1108 for 3 d. After the evaporation of the solvent, H2O (50 ml) was added to the residue, and org. phase
was extracted with AcOEt (3 ꢁ 30 ml). The combined org. layers were dried (Na2SO4). Evaporation of

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Helvetica Chimica Acta – Vol. 93 (2010)
the solvent and crystallization of the residue from AcOEt/hexane gave 9 (0.85 g, 95%). Yellow crystals.
M.p. 155 – 1578. IR (CH2Cl2): 3495, 2937, 1595, 1549, 1465, 1422, 1372, 1310, 1282, 1192, 1161, 1103, 1038,
1006. 1H-NMR (400 MHz, CDCl3): 7.10 (s, 1 arom. H); 6.16 (s, 1 arom. H); 4.54 (s, CH2O); 4.24 (s, CH2);
3.93 (s, MeO); 3.87 (s, MeO); 3.80 (s, MeO); 3.56 (s, MeO); 1.70 (br. s, OH). 13C-NMR (100 MHz,
CDCl3): 152.71 (C); 152.65 (C); 146.32 (C); 146.16 (C); 136.84 (C); 136.11 (C); 128.92 (C); 122.79 (C);
122.04 (C); 117.65 (C); 112.02 (CH); 111.55 (CH); 63.36 (MeO); 60.74 (MeO); 60.72 (MeO); 56.31
(MeO); 56.28 (CH2O); 39.50 (CH2). Anal. calc. for C18H19Br3O5: C 38.95, H 3.45; found: C 38.85, H 3.51.
General Procedure (GP) for Synthesis of Benzyl Methyl Ethers. 2,3-Dibromo-1-[2-bromo-3,4-
dimethoxy-6-(methoxymethyl)benzyl]-4,5-dimethoxybenzene (10). To a stirred soln. of 9 (0.40 g,
0.7 mmol) in THF (20 ml) were added NaH (0.04 g, 1.7 mmol) and Me2SO4 (0.11 g, 0.87 mmol) at 08.
The mixture was stirred at the same temp. for 1 h and then at r.t. for 24 h. After evaporation of the
solvent, H2O (30 ml) was added to the residue. The org. phase was extracted with AcOEt (3 ꢁ 30 ml).
The combined org. phases were dried (Na2SO4). Evaporation of the solvent and crystallization of the
residue from AcOEt/hexane afforded 10 (0.39 g, 97%). Yellow solid. M.p. 118 – 1208. IR (CH2Cl2): 2926,
2854, 1595, 1549, 1463, 1423, 1397, 1373, 1313, 1284, 1252, 1223, 1193, 1162, 1112, 1091, 1040, 1008.
1H-NMR (400 MHz, CDCl3): 7.01 (s, 1 arom. H); 6.15 (s, 1 arom. H); 4.24 (s, CH2); 4.20 (s, CH2); 3.90 (s,
MeO); 3.83 (s, MeO); 3.78 (s, MeO); 3.54 (s, MeO); 3.33 (s, CH2OMe). 13C-NMR (100 MHz, CDCl3):
152.63 (C); 152.46 (C); 146.30 (C); 146.19 (C); 136.23 (CH); 134.21 (CH); 129.56 (C); 122.71 (C); 121.86
(C); 117.53 (C); 112.37 (C); 112.06 (C); 72.95 (CH2O); 60.67 (MeO); 60.66 (MeO); 58.81 (MeO); 56.26
(MeO); 56.22 (MeO); 39.57 (CH2). Anal. calc. for C19H21Br3O5: C 40.10, H 3.72; found: C 39.97, H 3.73.
General Procedure (GP) for O-Demethylation of Aryl Methyl Ethers. 3,4-Dibromo-5-[2-bromo-3,4-
dihydroxy-6-(methoxymethyl)benzyl]benzene-1,2-diol (2). A soln. of 10 (0.40 g, 0.7 mmol) in CH2Cl2
(20 ml) was chilled to 08 under N2. To this soln. was added a soln. of BBr3 (0.5 ml, 1.32 g, 5.3 mmol) in
CH2Cl2 (15 ml) at the same temp. under N2. After the addition of BBr3 was completed, the mixture was
stirred at r.t. for 24 h. Then, it was cooled to 08, and to this mixture was added MeOH (10 ml) dropwise
for 10 min. The mixture was heated at 608 for 3 h. After evaporation of the solvent, AcOEt (40 ml) and
H2O (20 ml) were added to the residue. The org. layer was separated, and the H2O phase was extracted
with AcOEt (2 ꢁ 20 ml). The org. layers were combined and dried (Na2SO4). Evaporation of the solvent
gave 2 (0.30 g, 82%). Brownish solid. M.p. > 3008 ([4]: M.p. 5408). 1H-NMR (400 MHz, (CD3)2CO): 8.45
(m, 4 OH); 7.00 (s, 1 arom. H); 6.08 (s, 1 arom. H); 4.21 (s, CH2); 4.12 (s, CH2); 3.24 (s, MeO). 13C-NMR
(100 MHz, (CD3)2CO): 144.79 (C); 144.22 (C); 142.85 (C); 142.83 (C); 131.78 (C); 130.22 (C); 128.90
(C); 115.68 (CH); 115.63 (C); 114.39 (CH); 114.32 (C); 114.28 (C); 72.62 (CH2); 57.42 (MeO); 38.70
(CH2). Anal. calc. for C15H13Br3O5: C 35.12, H 2.55; found: C 35.18, H 2.60.
3,4-Dibromo-5-[2-bromo-3-(bromomethyl)-4,5-dihydroxybenzyl]benzene-1,2-diol (11). The O-de-
methylation method described for the synthesis of 2 was applied to 10 (0.40 g, 0.70 mmol); however, after
the reaction was completed, H2O instead of MeOH was added to the mixture at 08. The org. layer was
separated, and the H2O layer was extracted with AcOEt (2 ꢁ 50 ml). Combined org. layers were dried
(MgSO4), and evaporation of the solvent gave 11 (0.36 g, 90%). Brownish solid. M.p. > 2708 (dec.). IR
1
(acetone): 3384, 2921, 2845, 1693, 1604, 1579, 1492, 1468, 1400, 1351, 1278, 1204, 1172, 1093. H-NMR
(400 MHz, (CD3)2CO): 7.08 (s, 1 arom. H); 6.11 (s, 1 arom. H); 4.57 (s, CH2Br); 4.24 (s, CH2). 13C-NMR
(100 MHz, (CD3)2CO): 144.68 (C); 144.38 (C); 144.16 (C); 142.91 (C); 131.18 (C); 130.00 (C); 129.39
(C); 116.88 (CH); 115.79 (2 C); 114.29 (CH); 113.12 (C); 38.98 (CH2); 32.99 (CH2). Anal. calc. for
C14H10Br4O4: C 29.93, H 1.79; found: C 29.98, H 1.71.
2,6-Dibromo-3,5-dimethoxybenzaldehyde (13). To a stirred soln. of 12 (1.0 g, 6.02 mmol) in CHCl3
(30 ml) was added a soln. of Br2 (2.023 g, 12.6 mmol) in CHCl3 (10 ml) dropwise for 10 min at r.t. The
mixture was stirred at r.t. for 24 h. The evaporation of excess Br2 and solvent gave 13 (1.79 g, 92%).
Brownish solid. M.p. 218 – 2208 ([21]: M.p. 221 – 2228). 1H-NMR (400 MHz, CDCl3): 10.19 (s, CHO); 6.65
(s, 1 arom. H); 3.95 (s, 2 MeO). 13C-NMR (100 MHz, CDCl3): 191.80 (CO); 156.73 (2 C); 135.17 (C);
103.71 (2 C); 99.90 (CH); 57.08 (2 MeO).
(2,6-Dibromo-3,5-dimethoxyphenyl)methanol (14). To a stirred soln. of 13 (1.0 g, 3.09 mmol) in
THF/MeOH 1:1 (40 ml) was added NaBH4 (0.118 g, 3.12 mmol) in small pieces at 08. The mixture was
stirred at the same temp. for 30 min and then at r.t. for 24 h. After evaporation of the solvent, CH2Cl2
(50 ml) and H2O (50 ml) were added to the residue. The org. layer was separated, and H2O layer was

Helvetica Chimica Acta – Vol. 93 (2010)
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extracted with CH2Cl2 (2 ꢁ 40 ml). Combined org. layers were dried (Na2SO4). The evaporation of the
solvent and the crystallization of the residue with AcOEt/hexane gave 14 (0.96 g, 95%). Brown crystals.
M.p. 182 – 1848. IR (CH2Cl2): 3399, 3253, 2951, 2932, 1667, 1584, 1513, 1494, 1464, 1432, 1388, 1340, 1271,
1
1242, 1167, 1138, 1094, 1021. H-NMR (400 MHz, CDCl3): 6.50 (s, 1 arom. H); 5.07 (s, CH2); 3.91 (s,
2 MeO); 2.26 (br. s, OH). 13C-NMR (100 MHz, CDCl3): 156.43 (2 C); 140.19 (2 C); 106.13 (C); 97.19
(CH); 65.85 (CH2); 56.92 (2 MeO). Anal. calc. for C9H10Br2O3: C 33.16, H 3.09; found: C 33.15, H 3.08.
2,3-Dibromo-4,5-dimethoxy-1-(methoxymethyl)benzene (16). The GP described for the synthesis of
10 was applied to 6 (1.00 g, 3.1 mmol) to give 16 (1.00 g, 96% yield). Yellow crystals. M.p. 73 – 758 ([23]:
1
M.p. 71 – 728). H-NMR (400 MHz, CDCl3): 7.06 (s, 1 arom. H); 4.46 (s, CH2); 3.87 (s, MeO); 3.82 (s,
MeO); 3.47 (s, MeO). 13C-NMR (100 MHz, CDCl3): 152.87 (C); 146.85 (C); 135.54 (C); 121.85 (C);
115.02 (C); 111.42 (CH); 74.98 (CH2O); 60.73 (MeO); 58.97 (MeO); 56.40 (MeO).
2,4-Dibromo-1,5-dimethoxy-3-(methoxymethyl)benzene (17). The GP described for the synthesis of
10 was applied to 14 (0.70 g, 3.1 mmol) to give 17 (0.67 g, 96% yield). Brownish crystals. M.p. 125 – 1278.
IR (CH2Cl2): 3014, 2977, 2924, 1577, 1458, 1432, 1377, 1338, 1286, 1223, 1186, 1101, 1075, 944, 817.
1H-NMR (400 MHz, CDCl3): 6.51 (s, 1 arom. H); 4.84 (s, CH2); 3.90 (s, 2 MeO); 3.44 (s, MeO). 13C-NMR
(100 MHz, CDCl3): 156.29 (2 C); 137.78 (C); 107.22 (2C); 97.33 (CH); 74.06 (CH2O); 58.73 (MeO); 56.92
(2 MeO). Anal. calc. for C10H12Br2O3: C 35.32, H 3.56; found: C 35.19, H 3.54.
1,2,4-Tribromo-5,6-dimethoxy-3-(methoxymethyl)benzene (18). The GP described for the synthesis
of 10 was applied to 15 (1.00 g, 2.47 mmol) to give 18 (0.98 g, 94%). Yellow crystals. M.p. 88 – 908 ([22]:
M.p. 91 – 928). 1H-NMR (400 MHz, CDCl3): 4.85 (s, CH2); 3.89 (s, MeO); 3.88 (s, MeO); 3.46 (s, MeO).
13C-NMR (100 MHz, CDCl3): 152.32 (C); 150.92 (C); 134.36 (C); 124.15 (C); 122.10 (C); 121.99 (C);
75.70 (CH2); 61.11 (MeO); 61.05 (MeO); 58.94 (MeO).
Synthesis of Benzendiols 19, 20, and 21. The GP described above for the synthesis of 2 was applied to
16, 17, and 18 to give 19 (82% yield), 20 (79% yield), and 21 (95% yield), resp.
3,4-Dibromo-5-(methoxymethyl)benzene-1,2-diol (19). Brownish solid. M.p. 111 – 1138 ([24]: M.p.
112 – 1148). 1H-NMR (400 MHz, (CD3)2CO): 8.88 (br. s, OH); 8.33 (br. s, OH); 7.05 (s, 1 arom. H); 4.40
(s, CH2); 3.38 (s, MeO). 13C-NMR (100 MHz, (CD3)2CO): 144.95 (C); 143.89 (C); 130.85 (C); 114.77
(CH); 113.91 (C); 113.09 (C); 74.48 (CH2); 57.77 (MeO). Anal. calc. for C8H8Br2O3: C 30.80, H 2.58;
found: C 30.76, H 2.59.
4,6-Dibromo-5-(methoxymethyl)benzene-1,3-diol (20). Brownish solid. M.p. 59 – 618. IR (CH2Cl2):
3397, 2933, 1719, 1596, 1580, 1515, 1495, 1464, 1433, 1388, 1335, 1235, 1191, 1152, 1139, 1095, 1063, 1024,
949. 1H-NMR (400 MHz, CDCl3): 6.74 (s, 1 arom. H); 5.83 (br. s, 2 OH); 4.74 (s, CH2); 3.45 (s, MeO).
13C-NMR (100 MHz, CDCl3): 153.04 (2 C); 135.87 (C); 105.79 (2 C); 103.41 (CH); 74.40 (CH2); 58.71
(MeO). Anal. calc. for C8H8Br2O3: C 30.80, H 2.58; found: C 30.69, H 2.66.
3,4,6-Tribromo-5-(methoxymethyl)benzene-1,2-diol (21). Brownish solid. M.p. 125 – 1278 ([25b]:
M.p. 124 – 1258). 1H-NMR (400 MHz, (CD3)2CO): 6.04 (br. s, OH); 5.93 (br. s, OH); 4.81 (s, CH2); 3.46
(s, MeO). 13C-NMR (100 MHz, (CD3)2CO): 144.79 (C); 143.20 (C); 129.47 (C); 118.38 (C); 113.72 (C);
113.06 (C); 75.33 (CH2); 57.57 (MeO). Anal. calc. for C8H7Br3O3: C 24.58, H 1.81; found: C 24.64, H 1.79.
X-Ray Structure Determination for 8. For the crystal structure determination, the single-crystal of
compound 8 was used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer
(equipped with a two-dimensional area IP detector). The graphite-monochromatized MoKa radiation (l
0.71073 ꢄ) and oscillation scans technique with Dw ¼ 58 for one image were used for data collection. The
lattice parameters were determined by the least-squares method on the basis of all reflections with F2 >
2s(F2). Integration of the intensities, correction for Lorentz and polarization effects, and cell refinement
were performed using CrystalClear (Rigaku/MSC Inc., 2005) software [26]. The structures were solved
by direct methods using SHELXS-97 [27] and refined by a full-matrix least-squares procedure using the
program SHELXL-97 [27]. The H-atoms were positioned geometrically and refined using a riding model.
The final difference Fourier maps showed no peaks of chemical significance. Thermal ellipsoids in
ORTEP [28] plots represent a 40% probability.
Crystal Data for 8. C18H18O4Br4, crystal system, space group: monoclinic, P21/n; (no. 14); unit cell
dimensions: a ¼ 13.2050(2), b ¼ 10.4580(3), c ¼ 15.5470(4) ꢄ, b ¼ 100.50(3)8; volume: 2111.0(2) ꢄ3;
Z ¼ 4; calculated density: 1.94 mg/m3; absorption coefficient: 7.645 mmꢀ1; F(000): 1192; q range for data
collection 2.2 – 26.48; refinement method: full-matrix least-square on F2; data/parameters: 4317/239;

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Helvetica Chimica Acta – Vol. 93 (2010)
goodness-of-fit on F2: 1.392; final R indices [I > 2s(I)]: R1 ¼ 0.097, wR2 ¼ 0.152; R indices (all data): R1 ¼
0.139, wR2 ¼ 0.160; largest diff. peak and hole: 0.861 and ꢀ 0.851 e ꢄꢀ3
.
Compound 8 crystallizes in the monoclinic space group P21/n, with four molecules in the unit cell
(Fig. 2). The CꢀBr bond lengths are within the expected range (1.892(5) – 1.935(5) ꢄ). The X-ray
structure of 8 displayed the twisting of the two phenyl moieties with a dihedral angle of 86.9(2)8. The
data (CCDC-719647) can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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Received August 19, 2009