Multi-functionalization of gallic acid towards improved synthesis of α- and β-DDB

Article abstract of DOI:10.1016/j.tet.2004.11.083

The synthesis of mono-, di- and trisubstituted gallic acids and their ester with similar or different groups including different acetal and ketals is described. Regioselective bromination on two ortho-positions of methyl gallate, which is very crucial for many organic syntheses, was achieved in high yield and purity. The α- and β-DDB were synthesized in high overall yield and purity from the regioselective bromoderivatives.

Full text of DOI:10.1016/j.tet.2004.11.083

Tetrahedron 61 (2005) 1909–1918
Multi-functionalization of gallic acid towards improved synthesis
of a- and b-DDB
Ashraful Alam,a,† Yutaka Takaguchi,a Hideyuki Ito,b Takashi Yoshidab and Sadao Tsuboia,
*
aDepartment of Environmental Chemistry and Materials, Faculty of Environmental Science and Technology, Okayama University,
Okayama 700-8530, Japan
bFaculty of Pharmaceutical Science, Okayama University, Okayama 700-8530, Japan
Received 16 September 2004; accepted 30 November 2004
Available online 23 December 2004
Abstract—The synthesis of mono-, di- and trisubstituted gallic acids and their ester with similar or different groups including different acetal
and ketals is described. Regioselective bromination on two ortho-positions of methyl gallate, which is very crucial for many organic
syntheses, was achieved in high yield and purity. The a- and b-DDB were synthesized in high overall yield and purity from the regioselective
bromoderivatives.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
methylenedioxy-2,20-dimethoxycarbonylbiphenyl (b-DDB)
(Fig. 1) involves the proper functionalization of the gallic
acid unit.6,7 These DDBs are used in traditional Chinese
medicine as antihapetotoxic (liver injury), anticonvulsive
(cerebral protection) and also exhibit antitumor, antiHIV
and antifungal activities among other properties.7 Besides
these, different functionalized gallic acid units can be used
for the synthesis of a variety of alkyl and glycoside
derivatives of ellagic acid,8 which have many biological
activities such as antitumor, antiHIV, anticancer, antihepa-
tatic, etc.9 and are also the major component of many
cosmetics and skin care creams. The synthesis of different
biologically active natural polyhydroxystilbens10 and some
alkaloids11 also involved the utilization of a properly
functionalized gallic acid unit.
The preparation of alkylated polyphenol derivatives from
gallic acid has attracted the attention of synthetic chemists
for many years.1 This is mainly due to the fact that these
compounds have a variety of medicinal and industrial
applications, including their use as antioxidants2 and
mediators in modulation of the genotoxicity of food
carcinogens.3 Recently, these compounds have been
used as starting materials in the mesomorphic materials
engineering.4,5
The synthesis of different chiral biphenyl derivatives such as
4,40-dimethoxy-5,6,50,60-dimethylenedioxy-2,20-dimethoxy-
carbonylbiphenyl (a-DDB), 6,60-dimethoxy-4,5,40,50-di-
Figure 1. Gallic acid and a- and b-DDB.
Keywords: Gallic acid; Multi-functionalization; Regioselective bromination; a-DDB; b-DDB.
* Corresponding author. Tel./fax: C81 86 251 8898; e-mail: stsuboi6@cc.okayama-u.ac.jp
† On study leave from Department of Chemistry, Shahjalal University of Science and Technology, Sylhet-3114, Bangladesh.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.083

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A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
Scheme 1. Methoxylation and monobromination of methyl gallate.
So from the above discussion, it is known that the
functionalization of gallic acid or methyl gallate plays an
important role in the synthesis of a wide variety of
biologically active natural products.
finally, the reaction succeeded mostly by using 1,3-di-
bromo-5,5-dimethylhydantoin (DBDMH) as the bromi-
nating agent. Treatment of 3 with 0.50–0.58 mol equiv of
DBDMH in CHCl3 at room temperature yielded the
bromide in 95% conversion, but it was found to contain
the undesired dibromo ester (GC-MS, 1H NMR). The
desired monobromo component was then separated from
the undesired dibromo ester by selective hydrolysis. The
mixture of bromides obtained from 3 was treated with
2.0–2.5 equiv of LiOH in MeOH/H2O (1:1) at room
temperature for 6 h to result in selective hydrolysis of the
monobromo ester to the corresponding monobromo acid 4
(Scheme 1, 81% from 3). The undesired dibromo ester
remained unhydrolyzed and was separated easily by simple
column chromatography (15% from 3). Compound 5 gave
the corresponding bromo derivative 6 as a single product in
93% yield upon treatment with 0.5 equiv of DBDMH in
CHCl3.
So far, very few reports have appeared regarding the
functionalization of gallic acid or methyl gallate. Most of
them were concerned mainly with similar groups such as
long-chain alkyls, alkyl halides, alcohols12 and conjugated
enes.13 In this work, we wish to report a flexible route not
only for functionalization of the hydroxy groups, but also
for the regioselective bromination of two ortho-positions of
methyl gallate. This regioselective bromination plays an
important role in synthesis of different biologically active
biphenyl derivatives.6,7 This highly diversified functionali-
zations of methyl gallate will provide an easy access to the
synthesis of a variety of organic compounds, as well as a
useful data library. Similarly, these protection strategies can
also be used for other catechols or polyhydroxy aromatic
compounds, such as pyrogallol.
As mentioned before, regioselectively brominated deriva-
tives 11 and 14 (Scheme 2) are very potent for the synthesis
of many biologically active biphenyls. The regioselective
bromination at the 2- or 6-position are the key steps in all
reported syntheses. A mixture of 2-bromo, 6-bromo and
2,6-dibromo components were reported in low yield over
multi-steps procedure, using regioselective nitration–
reduction followed by the Sandmeyer reaction.6,7 Matsuoka
has reported a single debromination of 2,6-dibromo
derivatives with Zn and aqueous sodium hydroxide in
84% yield.16
2. Results and discussion
The starting material, methyl gallate 2, is commercially
available or can be prepared very easily by treating the
gallic acid with MeOH and H2SO4 followed by recrystalli-
zation from hot water in almost quantitative yield. The
4-MeO derivative 3 was prepared using the known method14
by treating with Li2CO3 and MeI in DMF at 55 8C, and at
the same time dimethoxy derivative 5 was formed as a
byproduct. Compound 5 can also be prepared by further
methoxylation of 3. But the monobromination of 3 was quite
difficult. Bromination with Br2 in various solvent systems
(CHCl3, CHCl3/H2O, CCl4, CCl4/H2O, acetic acid, dioxane,
diisopropyl amine/toluene,15 etc.) under different reaction
conditions was failed to give the desired monobromo
compound as a unique product rather than as an inseparable
mixture of the starting material, monobromo and dibromo
derivatives in varying ratios from 1:2:1 to 1:8:8. Then,
For the regioselective synthesis of bromo derivatives 11 and
14, 3-O-alkyl gallate 8 was prepared from 2 via the acetal 7.
Methylenedioxy protection of 4,5-dihydroxy of 8 provided
the fully protected methyl gallate 9 (Scheme 2). But the
regioselective bromination of 9 at C-6 (or C-2) by a variety
of ways (Br2/CH2Cl2/H2O, NBS/CH3SO3H, DBDMH/
CF3COOH, DBDMH/p-TsOH, etc.) failed. Treatment of 9
with Br2 in various reaction media resulted in very trace
conversion to the bromide. Though the conversion of the

A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
1911
Scheme 2. Routes for the preparation of regioselective bromo derivatives for the synthesis of DDB.a
reaction was increased to 100% by using organic acid17 as
additive, but an inseparable mixture of 6-Br and 2-Br
isomers was formed in 12:5 ratio (mixture of 11 and 14).
Finally, interestingly, we prepared both monobromo
regioisomers 11 and 14 in very good yield and purity18
using the same brominating agent, DBDMH by changing
the starting material. We did the bromination of 8 followed
by dioxy protection to 11 rather than bromination of 9 to 11.
Simple treatment of 8 with DBDMH in CHCl3 gave the
corresponding 6-bromo derivatives 10 (the position of
bromide was not confirmed at this stage but was confirmed
in the next step for compound 11b). Compounds 10 were
converted to the desired methylenedioxy protected com-
pound 11 and differently protected compound 12. The
benzyl deprotection of 9b provided methyl 3-hydroxy-4,5-
methylenedioxybenzoate 13, which upon regioselective
bromination at the 2-position yielded another desired
bromo isomer 14a that was converted to the corresponding
methyl and benzyl derivatives 14b, 14c, respectively. Thus,
compounds 11 and 14 were prepared from commercially
available methyl gallate 2 in excellent overall yield (11a,
82%; 11b, 79.5%; 14b, 71% from 2), much higher yield
than the reported one (lit.7 53 and 25% of 11a and 14b,
respectively). The position of the bromide in compounds 11
and 14 was confirmed by measuring the NOE effect of 11b
and 14c (Fig. 2).
The preparation of 6-Br derivatives 14 was carried out in
fewer steps via compounds 7 and 15 as shown in Scheme 3.
Unfortunately, neither 7 nor 15 gave the desired bromide
upon treatment with DBDMH and the starting material 2
was recovered. Upon treatment with Br2/iso-Pr2NH/toluene
7 also did not give the desired bromide, whereas 15 gave a
mixture of the bromide 16 and the starting material in low
yield (55%). This problem could not be solved even after
protecting the remaining –OH of 15. Finally, it was found
that selective bromination at C-2 goes well, if the 3,4-dioxy-
protection of 15 is changed to other acetals (17, 19). For the
acetalization of 3,4-dihydroxy group of 2, some ketones
were used in the presence of montmorrilonite clay, K10 or
KSF, but the yield of acetal 17 was poor, whereas that with
Ph2CCl2 gave acetal 19 in a moderate yield. Then, upon
treatment with DBDMH, 17 and 19 gave the corresponding
bromides 18 and 20 in very high yield and purity (18, 88%;
20, 100%, respectively). Now, the only remaining hydroxy
group of 20 (R]H) can be protected by desired groups and
similarly the existing dioxy-protection also can be changed
to other suitable group. For example, 14b can be prepared
Figure 2. The NOE study for the compounds 9b, 11b and 14c.

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A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
Scheme 3. Alternative route for the regioselective synthesis of 2-Br derivatives.
via 21. Thus, the 2-Br derivative can be obtained with a
variety of protecting groups, rather than only the reported
3,4-methylene acetal group (14).
Bromination of compound 5 (Scheme 1) and 22 (Scheme 4)
is particularly noteworthy. At first, the bromination at the
2-position (ortho-position of –OH) was tried using Br2/iso-
Pr2NH/toluene as the reported method.15 Though the yield
of 6 was satisfactory (68%, lit.15 74%), it was only 61%
yield of 23, and was found to be a mixture of mono- and
dibromo components in 1.5:1 ratio. In addition to the lower
yield, the Br2/iso-Pr2NH/toluene method is somewhat
tedious. Finally, treatment of 5 and 22 with DBDMH gave
the corresponding bromide 6 and 23 in excellent yield and
purity18 (93 and 98%, respectively).
We wished to functionalize the three –OH groups of methyl
gallate with three different protecting groups. For example,
the selective protection of only one –OH of 3 with
methoxymethyl– was unsuccessful. Using even less than
0.5 equiv of chloromethyl methyl ether (MOMCl) yielded a
mixture of mono-, di-MOM and the starting material 3.
Then for example, compound 22 was prepared from 8b in
good yield as shown in Scheme 4. The corresponding
bromide 23 was then prepared by simple treatment with
DBDMH in CHCl3 in almost quantitative yield. Now the
only remaining –OH of 22 or 23 can be protected with any
suitable protecting group as required. For example, treat-
ment of 22 or 23 with diethylcarbamoyl chloride gave the
corresponding carbamide 24 and 25 in 100 and 97% yield,
respectively (Scheme 4). These carbamides can be used
for the anionic Fries rearrangement, remote anionic Fries
rearrangement,19 and for further functionalization at the
2-position of 24.
2.1. Preparation of a- and b-DDB
The regioselective bromo derivatives 11a, 14b so far
obtained in excellent overall yield in Scheme 2 and/or
Scheme 3 underwent the Ullmann coupling smoothly and
resulted in a-DDB and b-DDB respectively (Scheme 5).
Treatment of 11a and 14b with activated20 Cu in DMF at
175–185 8C yielded the corresponding coupling product a-
and b-DDB in 85 and 65% yield, respectively. Thus, the
synthesis of a- and b-DDB was completed in 70 and 46%
Scheme 4. Multi-functionalization of methyl gallate.

A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
1913
Scheme 5. Preparation of a- and b-DDB.
overall yield from the commercially available 2, much
higher overall yield than that recently reported7 (21 and
13%, respectively21 from the same compound 2).
derivative, 3.0 equiv) in benzene (10 ml/mmol) was
refluxed for 16–20 h with azeotropic removal of the
EtOH/benzene mixture by using the Dean Stark trap.
After completion, the reaction mixture was filtered over
celite and the solvent was removed and directly put on a
silica gel column eluted with 10–15% EtOAc in hexane.
In summary, a wide variety of functionalized/protected
methyl gallates was prepared in very good yield and purity.
Regioselective bromo derivatives with different protecting
groups have also been prepared in very good to excellent
yield and purity. These brominations were achieved by the
simple addition of solid DBDMH in CHCl3 at room
temperature, which is particularly suitable for a small-
scale reaction compared to the other methods utilizing
liquid molecular bromine. Besides the synthesis of a- and
b-DDB in very high overall yield, these functionalized
methyl gallate or bromo derivatives can be served as an
important precursor for the synthesis of many other
biologically active organic molecules as well as other
biphenyl derivatives (DDB analogues, Fig. 1) which may
have some biological importance.
3.2.1. Methyl 3-hydroxy-4,5-(ethoxymethylenedioxy)-
benzoate (7). Compound 2 (2.50 g, 13.58 mmol),
(EtO)3CH, (6.03 g, 40.74 mmol) and Amberlyst 15E
(62.0 mg) was treated as mentioned in Section 3.2 and
yielded 3.21 g (98.5% lit.22 52%) of 7 as a white solid; mp
91–92 8C; IR (ATR): 3351, 1709, 1618, 1438, 1316, 1254,
1081, 1038, 765 cmK1; 1H NMR (CDCl3) d 1.28 (t, 3H, JZ
7.1 Hz), 3.75 (q, 2H, JZ7.1 Hz), 3.88 (s, 3H), 5.56 (bs, 1H),
6.96(s, 1H), 7.19 (d, 1H, JZ1.5 Hz), 7.39 (d, 1H, JZ
1.8 Hz); 13C NMR (CDCl3) d 14.68, 52.38, 59.71, 102.71,
113.96, 120.04, 124.03, 137.08, 138.68, 147.14, 166.95;
GC-MS m/z (%): 240 (M, 15), 209 (5), 195 (23), 184 (39),
153 (100). Spectral data were identical with the reported
data.22
3. Experimental
3.1. General
3.2.2. Methyl 2-bromo-3,4-(ethoxymethylenedioxy)-5-
benzyloxybenzoate (12a). Using the similar procedure as
of 7, 12a was obtained in 92% yield from 10a as white solid;
mp 80–81 8C; IR (ATR): 1722, 1432, 1318, 1171, 1081,
1035, 938, 752, 700 cmK1; 1H NMR (CDCl3,) d 1.28 (t, 3H,
JZ7.1 Hz), 3.73 (q, 2H, JZ7.1 Hz); 13C NMR (CDCl3–
CD3OD) d 14.68, 52.28, 59.85, 71.79, 94.16, 114.41,
119.91, 124.17, 127.65, 128.32, 128.59, 135.90, 137.24,
140.43, 146.57, 165.41. Anal. Calcd for C18H17BrO6: C,
52.83; H, 4.19; Found: C, 52.62; H, 4.35.
All moisture-sensitive reactions were carried out under
nitrogen atmosphere using oven-dried glassware. Solvents
were dried over standard drying agents. Reactions were
monitored on TLC on silica gel 60 F254 and visualized under
UV light and/or 5% ethanolic solution of phosphomolybdic
acid. Flash chromatography was performed on silica gel
(Merck, 60N, spherical, neutral, 40–50 mash). Melting
points were determined with a Mel-TEMP apparatus. IR
was recorded on a Thermo Nicolet Avatar 360T2 instrument
1
using either KBr or ATR. H NMR (300 MHz) and 13C
3.2.3. Methyl-3-hydroxy-4,5-(p-methoxybenzylmethyl-
enedioxy)benzoate (15). Compound
NMR (75 MHz) were recorded by JEOL AL 300 instru-
ment. GC-MS was studied in a SHIMADZU GCMS-
QP5000 instrument (column length 30 m, Idm 0.25 mm,
column temperature 50–250 8C). Elemental analysis of all
the new compounds was carried out by Perkin Elmer 2400
series II CHNS/O analyzer, whereas the spectral data of
the known compounds were matched with the references
cited.
2
(2.00 g,
10.9 mmol) was treated with p-anisaldehyde dimethylacetal
(6.83 g, 3.0 equiv) and Amberlyst 15E (50 mg) in benzene
(80 ml) as mentioned in Section 3.2 to give the compound
15 (2.78 g, 85%) as a slight yellow solid; mp 128–131 8C;
IR (ATR): 3321, 1684, 1634, 1617, 1519, 1450, 1341, 1257,
1170, 1077, 1026, 1004, 832, 726 cmK1; 1H NMR (CDCl3)
d 3.84 (s, 3H), 3.87 (s, 3H), 5.20 (bs, 1H), 6.95 (d, 2H, JZ
9.0 Hz), 7.00 (s, 1H), 7.17 (d, 1H, JZ1.5 Hz), 7.34 (d, 1H,
JZ1.5 Hz) 7.50 (d, 2H, JZ8.7 Hz); 13C NMR (CDCl3) d
52.26, 55.36, 102.98, 111.93, 114.11, 124.11, 127.34,
128.04, 138.67, 138.84, 148.91, 161.35, 166.84. Anal.
Calcd for C16H14O6: C, 63.57; H, 4.67; Found: C, 63.18; H,
4.33.
3.2. General procedure for the Amberlyst 15E catalyzed
reaction of acetals with polyphenols
A mixture of compound 2 or 10, Amberlyst 15E (5 mg/
mmol), and appropriate protecting reagent (diethyl acetal

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A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
3.3. General procedure of bromination by 1,3-dibromo-
5,5-dimethylhydantoin (DBDMH)
145.67, 165.94; GC-MS m/z (%): 278 (M, 50), 276 (M,
51), 263 (5), 261 (5), 247 (62), 245 (61), 53 (100).
Solid DBDMH (0.50–0.58 mol equiv) was added in part
into the solution of starting material (Ar-OH) in CHCl3
(5–7 ml/mmol) at room temperature. Upon addition of the
DBDMH, the solution became red or deep brown colored,
the next portion of DBDMH was added after the
disappearance of color and so on. The progress of the
reaction was monitored by GC-MS, and sometimes can
easily be understood by observing the persistence of the
color of the reaction mixture (in case of slight excess
DBDMH used). After completion of the reaction, removal
of the solvent followed by the separation of the solid
byproduct (derived from DBDMH) by simple filtration
provided the almost pure bromo product. For the com-
pounds with low solubility, 10% aq solution of sodium
hydrosulfite (Na2S2O4) was added into the reaction mixture
and the organic layer (CHCl3) was separated that yielded the
almost pure product. The crude obtained in both cases were
almost pure and was used in the next step without further
purification, or a simple column wash gave pure product.
3.3.4. Methyl 2-bromo-3,4-dihydroxy-5-benzyloxy-
benzoate (10b). Following the similar procedure as
preparation of 10a, 10b was prepared in 95% yield from
8b as a light yellow crystal; mp 116–118 8C; IR (ATR):
1
3370, 1712, 1342, 1222, 1000 cmK1; H NMR (CDCl3) d
3.90 (s, 3H), 5.14 (s, 2H), 5.91 (s, 1H), 5.92 (s, 1H), 7.27 (s,
1H), 7.38–7.52 (m, 5H); 13C NMR (CDCl3–CD3OD) d
52.14, 71.34, 103.24, 108.31, 121.44, 127.96, 128.45,
128.62, 133.74, 137.64, 142.61, 144.93, 167.37. Anal.
Calcd for C15H13BrO5: C, 51.01; H, 3.71. Found: C, 49.90;
H, 3.77.
3.3.5. Methyl 2-bromo-3-hydroxy-4,5-methylenedioxy-
benzoate (14a). Using the general procedure in Section
3.3 (timeZ10 h), 14a was obtained from 13 in 95% yield as
crystal; mp 110–113 8C; IR (ATR): 3426, 1707, 1505, 1423,
1360, 1302, 1218, 1074, 1030, 935 cmK1 1H NMR
;
(CDCl3) d 3.90 (s, 3H), 5.89 (s, 1H), 6.10 (s, 2H), 7.11 (s,
1H); 13C NMR (CDCl3–CD3OD) d 52.43, 102.93, 104.62,
105.57, 124.00, 137.29, 137.62, 147.97, 165.49; GC-MS
m/z (%): 276 (M, 49), 274 (M, 51), 245 (91), 243 (90), 77
(83), 53 (100). Anal. Calcd for C9H7BrO5: C, 39.30; H,
2.57. Found: C, 39.50; H, 2.45.
3.3.1. 2-Bromo-3,5-dihydroxy-4-methoxybenzoic acid
(4). The compound 3 gave corresponding bromide upon
treatment with 0.58 mol equiv of DBDMH as described in
Section 3.3. The bromide was found to contain 15% of
dibromo derivative (GC-MS, 1H NMR). The bromide
mixture was then treated with 2.5 equiv of LiOH in
MeOH/H2O (1:1) at rt for 6 h which resulted in selective
hydrolysis of the desired mono bromo ester to correspond-
ing acid 4, whereas the dibromo ester derivative remained
unhydrolyzed and thus was separated by silica gel column
chromatography (20–25% EtOAc in hexane). (81% of 4
from 3). Light brown solid; mp 127–135 8C (decomp.); IR
(ATR): 3452, 2946, 1692, 1575, 1422, 1334, 1235, 1063,
3.3.6. Methyl 2-bromo-3-hydroxy-4,5-(methylphenyl-
methylenedioxy)benzoate (18). Using the general pro-
cedure in Section 3.3 (timeZ1 h), 18 was obtained from 17
in 88% as thick oil. IR (ATR): 3469, 1709, 1609, 1493,
1
1436, 1368, 1212, 1137, 923, 766, 698 cmK1; H NMR
(CDCl3) d 2.05 (s, 3H), 3.88 (s, 3H), 5.84 (s, 1H), 7.11 (s,
1H), 7.37–7.40 (m, 3H), 7.57–7.61 (m, 2H); 13C NMR
(CDCl3) d 27.04, 39.41, 104.82, 120.17, 123.58, 124.82,
129.31, 137.12, 139.97, 147.65, 165.57; GC-MS m/z (%):
366 (M, 2), 364 (M, 2), 351 (0.7), 349 (0.7), 335 (2), 333 (2),
264 (5), 262 (5), 233 (2), 231 (2), 103 (100). Anal. Calcd for
C16H13BrO5: C, 52.62; H, 3.59. Found: C, 52.68; H, 3.43.
1
980, 804 cmK1; H NMR (CDCl3–CD3OD) d 3.95 (s, 3H),
7.12 (S, 1H); 13C NMR (CDCl3–CD3OD) d 60.34, 99.61,
110.71, 127.30, 138.18, 147.69, 148.55, 168.17. Anal. Calcd
for C8H7BrO5: C, 36.53; H, 2.68; Found: C, 36.42; H, 2.37.
3.3.7. Methyl 2-bromo-3-hydroxy-4-methoxy-5-benzyl-
oxybenzoate (23). Compound 22 (505 mg, 1.75 mmol) in
CHCl3 (10 ml) was added 250 mg (0.87 mmol) DBDMH at
once and stirred at room temperature for 16 h. Then the
solvent was evaporated in vacuo. and purified as mentioned
in Section 3.3 gave 622 mg (98%) of 23 as a colorless
crystal; mp 123–125 8C; IR (KBr): 3324, 1721, 1573, 1489,
3.3.2. Methyl 2-bromo-3-hydroxy-4,5-dimethoxybenzo-
ate (6). According to Ref. 15, 6 was obtained in 68% from 5;
but treatment of 5 with 0.5 equiv of DBDMH as described in
Section 3.3 gave 93% of 6 as a slight brown crystal; mp
116–118 8C (lit.15 113 8C); IR (ATR): 3370, 1712, 1572,
1
1442, 1222, 1000, 729 cmK1; H NMR (CDCl3) d 3.89 (s,
3H), 3.92 (s, 3H), 3.97 (s, 3H), 6.22 (s, 1H), 7.05 (s, 1H); 13C
NMR (CDCl3) d 52.44, 56.14, 61.13, 101.34, 107.03,
126.84, 138.69, 147.35, 150.96, 166.27; GC-MS m/z (%):
292 (M, 96), 290 (M, 85), 277 (27), 275 (29), 261 (50), 259
1441, 1351, 1228, 1142, 1098, 995 cmK1 1H NMR
;
(CDCl3) d 3.91 (s, 3H), 3.98 (s, 3H), 5.12 (s, 2H), 6.27 (s,
1H), 7.14 (s, 1H), 7.37–7.42 (m, 5H); 13C NMR (CDCl3) d
52.44, 61.21, 71.13, 101.51, 108.62, 126.72, 127.49, 128.28,
128.64, 135.93, 139.11, 147.51, 159.92, 166.20; GC-MS
m/z (%): 368 (M, 0.4), 366 (M, 0.4), 337 (0.2), 335 (0.2),
287 (0.9), 91 (100). Anal. Calcd for C16H15BrO5: C, 52.34;
H, 4.12. Found: C, 52.34; H, 4.01.
1
(53), 93 (49), 66 (89), 53 (100). The H NMR data was
identical with the reported data.15
3.3.3. Methyl 2-bromo-3,4-dihydroxy-5-methoxybenzo-
ate (10a). Using the general procedure in Section 3.3, 8a
(850 mg, 4.20 mmol) was treated with 0.51 equiv of
DBDMH in CHCl3 (15 ml) for 24 h yielded 10a (1.16 g,
98%) as a slight yellow crystal; mp 140–142 8C; IR (ATR):
3461, 3341, 1717, 1601, 1429, 1292, 1210, 1101, 1018, 923,
3.4. General procedure for the methoxylation
The hydroxy starting materials were treated with MeI (2.0–
2.5 equiv), K2CO3 (2.0–2.5 equiv) in DMF (5–7 ml/mmol)
at 55–60 8C for 4–14 h. The crude was extracted with
diethyl ether, washed with brine, dried over MgSO4 and
1
776 cmK1; H NMR (CDCl3) d 3.91 (s, 3H), 3.94 (s, 3H),
5.84 (s, 1H), 5.92 (s, 1H), 7.18 (s, 1H); 13C NMR (CDCl3) d
52.30, 56.42, 103.26, 107.06, 121.81, 136.68, 141.36,

A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
1915
concentrated. The crude was almost pure and a simple
column wash gave the pure product.
DBDMH as mentioned in Section 3.3 for 2 h, yielded the
corresponding bromo derivative (100%), which upon
methoxylation as the general procedure in Section 3.4
gave the compound 20 (938 mg, 99%) as a slight brown
solid; mp 68–72 8C; IR (ATR): 1731, 1596, 1478, 1434,
3.4.1. Methyl 3,5-dihydroxy-4-methoxybenzoate (3).
Compound 3 was prepared as mentioned in Ref. 14
(2.5 equiv MeI, 2.5 equiv Li2CO3, in DMF at 50–55 8C
for 18 h) in 61% yield along with 12% compound 5. Light
yellow colored solid; mp 143–146 8C (lit.10 148 8C); IR
(ATR): 3409, 1707, 1598, 1505, 1432, 1363, 1272, 1164,
1004, 749 cmK1; 1H NMR (CDCl3) d 3.88 (s, 3H), 3.96 (s,
3H), 5.61 (s, 2H), 7.23 (s, 2H); 13C NMR (CDCl3–CD3OD):
51.88, 60.13, 108.99, 125.02, 139.32, 149.66, 167.37; GC-
MS m/z (%): 198 (M, 79), 183 (48), 167 (100), 155 (22).
Spectral data were identical with the reported data.10
1366, 1284, 1206, 1095, 1042, 1028, 918, 780, 699 cmK1
;
1H NMR (CDCl3) d 3.88 (s, 3H), 4.09 (s, 3H), 7.08 (s, 1H),
7.53–7.40 (m, 6H), 7.53–7.56 (m, 4H); 13C NMR (CDCl3) d
52.36, 60.37, 105.63, 109.00, 119.06, 126.25, 126.29,
128.33, 128.37, 128.43, 129.54, 139.05, 140.07, 140.85,
147.89, 166.29. Anal. Calcd for C22H17BrO5: C, 59.88; H,
3.88. Found: C, 60.17; H, 3.90.
3.4.6. Methyl 3-hydroxy-4-methoxy-5-benzyloxybenzo-
ate (22). Among several runs, the best result was obtained
by treating 8b (2.50 g, 9.12 mmol), Li2CO3 (1.01 g,
1.5 equiv), MeI (2.0 equiv), in DMF (50 ml) at 55–60 8C
for 16 h under nitrogen atmosphere. After completion, the
reaction mixture was extracted with Et2O, and the organic
layer was washed with brine, dried over MgSO4 and
concentrated in vacuo. Chromatographic separation (20%
EtOAc in hexane) yielded 2.07 g (78%) of 22 along with
554 mg (20%) of undesired dimethoxy derivative as a
colorless solid; mp 108–111 8C; IR (ATR): 3359, 1703,
3.4.2. Methyl 3-hydroxy-4,5-dimethoxybenzoate (5).
Compound 5 was obtained as a side product during the
preparation of compound 3 from 2 (12%). This was also
prepared by treating 3 with 1.0 equiv of K2CO3 and
1.0 equiv of MeI in DMF at 50–55 8C. The resulted mixture
of starting material, desired dimethoxy and undesired
trimethoxy derivatives was separated by silica gel column
to give 5 as colorless crystal; mp 73–75 8C (lit.22 73 8C); IR
(KBr): 3404, 3219, 1696, 1457, 1346, 1218, 1092, 769 cmK1
;
1
1589, 1504, 1438, 1355, 1228, 1089, 757 cmK1; H NMR
1H NMR (CDCl3) d 3.89 (s, 3H), 3.91 (s, 3H), 3.96 (s, 3H),
5.85 (s, H), 7.20 (d, 1H, JZ2.1 Hz), 7.31 (d, 1H, JZ
2.1 Hz); 13C NMR (CDCl3–CD3OD) d 52.15, 55.96, 60.93,
105.57, 109.88, 125.53, 139.44, 148.95, 151.91, 166.67;
GC-MS m/z (%): 212 (M, 100), 197 (64), 181 (66), 151 (20),
141 (40). Spectral data were identical with the reported
data.23
(CDCl3) d 3.88 (s, 3H), 3.92 (s, 3H), 5.14 (s, 2H), 5.86 (s,
1H), 7.29 (d, 1H, JZ1.8 Hz), 7.32 (d, 1H, JZ1.8 Hz), 7.34–
7.47 (m, 5H); 13C NMR (CDCl3) d 52.17, 61.03, 70.92,
107.03, 110.04, 125.46, 127.52, 128.14, 128.59, 136.31,
139.81, 149.06, 150.93, 166.61; GC-MS m/z (%): 288, (M,
1.7), 257 (0.7), 141 (0.8), 91 (100). Anal. Calcd for
C16H16O5: C, 66.66; H, 5.59. Found: C, 66.55; H, 5.52.
3.4.3. Methyl 3-methoxy-4,5-dihydroxybenzoate (8a).
Using the general procedure in Section 3.4, compound 7
gave the corresponding methoxy derivative, which upon
treatment with 2 N aq HCl at room temperature for 2 h in
MeOH gave 8a (99% yield over two steps) as a colorless
crystal; mp 115–119 8C; IR (ATR): 3382, 1708, 1593, 1506,
3.5. General procedure for benzyloxylation
The hydroxy starting materials were treated with 2.0 equiv
of BnCl, 2.0 equiv of K2CO3 in DMF (10 ml/mmol) at 70 8C
for 12–14 h. The crude was extracted with diethyl ether, and
the organic layer was washed with brine, dried over MgSO4
and concentrated. The crude was almost pure and a simple
column wash gave the pure product.
1
1436, 1243, 1161, 1058, 1000, 964, 726 cmK1; H NMR
(CDCl3) d 3.88 (s, 3H), 3.92 (s, 3H), 5.49 (s, 1H), 5.86 (s,
1H), 7.21 (d, 1H, JZ1.8 Hz), 7.34 (d, 1H, JZ1.8 Hz); 13C
NMR (CDCl3–CD3OD) d 51.85, 55.96, 104.94, 110.78,
120.38, 138.51, 144.21, 147.18, 167.56; GC-MS m/z (%):
198 (M, 44), 168 (100), 167 (52), 140 (25), 53 (33). Spectral
data were identical with the reported data.24
3.5.1. Methyl 3-benzyloxy-4,5-dihydroxybenzoate (8b).
Using the general method in Section 3.5, compound 7 gave
the corresponding benzyloxy derivative, which upon
treatment with 2 N aq HCl at room temperature for 2 h in
MeOH gave 8b in 100% yield over two steps as colorless
solid; mp 142–145 8C (lit.23 145–147 8C); IR (ATR): 3412,
3.4.4. Methyl 2-bromo-3-methoxy-4,5-methylenedioxy-
benzoate (14b). Using the general method in Section 3.4,
2.32 g (95%) of 14b was obtained from 2.33 g of 14a.
Compound 14b was also prepared from 21 in 85% yield
using the general procedure in Section 3.6. White solid; mp
87–88 8C (lit.7a 82–83 8C); IR (ATR): 1721, 1431, 1282,
3342, 1686, 1434, 1326, 1239, 1055, 744 cmK1; H NMR
1
(CDCl3) d 3.87 (s, 3H), 5.14 (s, 2H), 5.36 (s, 1H), 5.84 (s,
1H), 7.31 (d, 1H, JZ1.8 Hz), 7.35 (d, 1H, JZ1.8 Hz), 7.39–
7.43 (m, 5H); 13C NMR (CDCl3–CD3OD) d 51.76, 71.03,
106.36, 110.92, 120.36, 127.71, 128.06, 128.38, 136.08,
138.62, 144.33, 167.33; GC-MS m/z (%): 274 (M, 0.5), 243
(0.4), 127 (0.6), 91 (100). Spectral data were identical with
the reported one.23
1
1090, 1043, 942 cmK1; H NMR (CDCl3) d 3.89 (s, 3H),
4.02 (s, 3H), 6.04 (s, 2H), 7.02 (s, 1H); 13C NMR (CDCl3) d
52.41, 60.28, 102.38, 105.50, 109.12, 126.39, 140.50,
148.32, 166.24; GC-MS m/z (%): 290 (M, 62), 288 (M,
73), 259 (91), 257 (95), 217 (6), 215 (6), 201 (7), 199 (7),
143 (30), 77 (100), 53 (79). Anal. Calcd for C10H9BrO5: C,
41.55; H, 3.14. Found: C, 41.53; H, 3.00.
3.5.2. Methyl 2-bromo-3-benzyloxy-4,5-methylenedioxy-
benzoate (14c). Using the general procedure in Section 3.5,
1.20 g (w100%) of 14c was obtained from 904 mg
(3.28 mmol) of 14a as a white solid; mp 70–72 8C; IR
(ATR): 1713, 1431, 1364, 1282, 1242, 1176, 1096, 1040,
3.4.5. Methyl 2-bromo-3-methoxy-4,5-(diphenylmethyl-
enedioxy)benzoate (20). Compound 19 (750 mg,
2.15 mmol) was treated with 307 mg (0.5 equiv) of
1
944 cmK1; H NMR (CDCl3) d 3.89 (s, 3H), 5.25 (s, 2H),

1916
A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
6.03 (s, 2H), 7.25 (s, 1H), 7.32–7.41 (m, 3H), 7.47–7.51 (m,
2H); 13C NMR (CDCl3) d 52.36, 74.23, 102.36, 105.76,
109.84, 126.17, 126.62, 128.02, 128.25, 128.37, 136.27,
139.62, 140.92, 148.11, 166.14; GC-MS m/z (%): 366 (M,
0.4), 364 (M, 0.4), 335 (0.2), 333 (0.2), 285 (1.3), 91 (100).
Anal. Calcd for C16H13BrO5: C, 52.62; H, 3.59. Found: C,
52.80; H, 3.50.
7.32 (s, 1H), 7.35–7.42 (m, 5H); 13C NMR (CDCl3) d 52.26,
71.81, 94.69, 102.32, 114.73, 124.26, 127.69, 128.36,
128.63, 135.92, 138.79, 141.09, 148.22, 165.36; GC-MS
m/z (%): 366 (M, 0.6), 364 (M, 0.6), 335 (0.2), 333 (0.2),
149 (0.5), 147 (0.5), 91 (100). Anal. Calcd for C16H13BrO5:
C, 52.62; H, 3.59. Found: C, 52.85; H, 3.50.
3.6.5. Methyl 2-bromo-4,5-(biphenylmethylenedioxy)-
benzoate (12b). Compound 10b (680 mg, 1.32 mmol) was
treated with K2CO3 (3.0 equiv) and Ph2CCl2 (1.3 equiv) in
CH3CN (10 ml) at room temperature for 21 h under nitrogen
atmosphere. After completion, the reaction mixture was
extracted with EtOAc followed by usual workup and silica
gel column chromatography gave 668 mg (62%) isolated
desired product 12b. Light yellow needles; mp 155–156 8C;
IR (ATR): 1722, 1432, 1318, 1171, 1081, 1035, 938, 752,
3.6. General procedure for the methylenedioxy-
protection
A mixture of starting material (dihydroxy compound)
(1 equiv), KF (5 equiv) and CH2I2 (1.5 equiv) in DMF
(8–9 ml/mmol) was heated at 110 8C for overnight. After
completion, the reaction mixture was extracted with diethyl
ether, washed with brine, dried over MgSO4, and condensed
in vacuo. Silica gel column chromatography eluted with
20–25% EtOAc in hexane gave the pure desired product.
1
700 cmK1; H NMR (CDCl3) d 3.86 (s, 3H), 5.21 (s, 2H),
7.28 (s, 1H), 7.32–7.40 (m, 11H), 7.55–7.59 (m, 4H); 13C
NMR (CDCl3) d 52.22, 71.95, 94.78, 115.17, 118.90,
124.07, 126.16, 126.41, 127.63, 128.24, 128.33, 128.57,
129.52, 136.16, 138.46, 138.94, 140.92, 165.48. Anal. Calcd
for C28H21BrO5: C, 65.00; H, 4.09. Found: C, 65.20; H,
4.10.
3.6.1. Methyl 3-methoxy-4,5-methylenedioxybenzoate
(9a). Using the general procedure in Section 3.6, 625 mg
(85%) of 9a was obtained from 693 mg (3.50 mmol) of 8a
as a transparent crystal; mp 85–87 8C (lit.7a 88–89 8C); IR
(ATR): 1704, 1632, 1431, 1366, 1328, 1239, 1175, 1106,
1037, 761 cmK1; 1H NMR (CDCl3) d 3.88 (s, 3H), 3.94 (s,
3H), 6.05 (s, 2H), 7.20 (d, 1H, JZ1.5 Hz), 7.33 (d, 1H, JZ
1.5 Hz); 13C NMR (CDCl3) d 52.08, 56.45, 102.22, 103.77,
109.85, 124.30, 139.37, 143.19, 148.58, 166.29; GC-MS
m/z (%): 210 (M, 59), 179 (100), 151 (32), 95 (21). 1H NMR
data was identical with the reported data.7a
3.6.6. Methyl 3-hydroxy-4,5-methylenedioxybenzoate
(13). TiCl4 (0.08 ml, 1.2 equiv) was added in 202 mg
(0.71 mmol) of 9b in CHCl3 (5 ml), at room temperature
and the reaction mixture was stirred for 12 h. After
completion, it was extracted with EtOAc, washed with
brine, dried over MgSO4 and purified by column chroma-
tography eluted with 25–30% EtOAc in hexane yielded
116 mg (90%) isolated 13 as colorless solid; mp 168–172 8C
(lit.24 164 8C); IR (ATR): 3313, 1684, 1637, 1448, 1353,
3.6.2. Methyl 3-benzyloxy-4,5-methylenedioxybenzoate
(9b). Using the general procedure in Section 3.6, 394 mg
(90%) of 9b was obtained from 420 mg (1.53 mmol) of 8b
as a transparent solid; mp 70–73 8C; IR (ATR): 1713, 1430,
1364, 1326, 1247, 1101, 751, 697 cmK1; 1H NMR (CDCl3)
d 3.88 (s, 3H), 5.20 (s, 2H), 6.06 (s, 2H), 7.21 (d, 1H, JZ
1.5 Hz), 7.41 (d, 1H, JZ1.8 Hz), 7.35–7.46 (m, 5H); 13C
NMR (CDCl3) d 52.10, 71.46, 102.18, 104.00, 112.11,
124.33, 127.65, 128.19, 128.57, 136.21, 139.87, 142.21,
148.85, 166.26; GC-MS m/z (%): 286 (M, 6), 255 (2),
91(100). Spectral data were identical with the reported
data.26
1
1192, 1170, 1063, 1033, 760 cmK1; H NMR (CDCl3) d
3.87 (s, 3H), 5.07 (bs, 1H), 6.05 (s, 2H), 7.15 (d, 1H, JZ
1.2 Hz), 7.31 (d, 1H, JZ1.5 Hz); 13C NMR (CDCl3–
CD3OD) d 51.89, 101.79, 102.03, 113.78, 123.71, 128.00,
140.17, 148.62, 166.98; GC-MS m/z (%): 196 (M, 39), 165
(100), 137 (26), 53 (31). Spectral data were identical with
the reported data.25
3.6.7. Methyl 2-bromo-3-hydroxy-4,5-(p-methoxybenzyl-
methylenedioxy)benzoate (16). Compound 16 was pre-
pared in 55% yield from 15 according to Ref. 15. Light
brown colored solid; mp 121–123 8C; IR (ATR): 3345,
1670, 1599, 1577, 1511, 1427, 1332, 1258, 1214, 1162,
1045, 1019, 925, 829, 771 cmK1; 1H NMR (CDCl3) d 3.84
(s, 1H), 3.90 (s, 3H), 5.89 (bs, 1H), 6.95 (s, 1H), 6.97 (s, 1H),
7.06 (s, 1H), 7.12 (s, 1H), 7.48 (s, 1H), 7.51 (s, 1H); 13C
NMR (CDCl3–CD3OD) d 52.07, 55.03, 96.41, 103.24,
105.18, 111.96, 113.32, 113.73, 113.80, 124.85, 127.85,
127.77, 147.41, 161.16. Anal. Calcd for C16H13BrO6: C,
50.42; H, 3.44; Found: C, 50.29; H, 3.12.
3.6.3. Methyl 2-bromo-3,4-methylenedioxy-5-methoxy-
benzoate (11a). Using the general procedure in Section 3.6,
100 mg of isolated 11a (84%) was obtained from 89 mg
(0.32 mmol) of 10a, as a colorless solid; mp 101–102 8C
(lit.7a 104–105 8C); IR (ATR): 1724, 1433, 1324, 1248,
1
1175, 1107, 1041, 935 cmK1; H NMR (CDCl3) d 3.91 (s,
3H), 3.92 (s, 3H), 6.12 (s, 2H), 7.24 (s, 1H); 13C NMR
(CDCl3) d 52.25, 56.75, 94.40, 102.37, 112.39, 124.24,
138.29, 142.16, 147.97, 165.42; GC-MS m/z (%): 290 (M,
42), 288 (M, 50), 259 (69), 257 (68), 231 (5), 229 (5), 217
(5), 215 (5), 201 (16), 199 (16), 77(100). Anal. Calcd for
C10H9BrO5: C, 41.55; H, 3.14. Found: C, 41.40; H, 2.98.
3.6.8. Methyl 3-hydroxy-4,5-(methyl, phenyl methylene-
dioxy)benzoate (17). Compound 2 (200 mg, 1.08 mmol),
montmorillonite clay K10 (117 mg) and acetophenone
(2.0 equiv) in 15 ml of benzene was refluxed for 16 h with
removal of generated water by passing through a trap of 3A
molecular sieves. After completion, the reaction mixture
was filtered over celite, dried over MgSO4, and removed the
solvent in vacuo. Separation by silica gel column chroma-
tography (eluted with 20% EtOAc in hexane) provided
3.6.4. Methyl 2-bromo-3,4-methylenedioxy-5-benzyloxy-
benzoate (11b). Using the general procedure in Section 3.6,
1.06 g (85%) of 11b was obtained from 1.20 g (3.40 mmol)
of 10b as a colorless solid; mp 77–80 8C; IR (ATR): 1721,
1430, 1343, 1322, 1174, 1094, 1040, 939, 747, 700 cmK1
;
1H NMR (CDCl3) d 3.89 (s, 3H), 5.17 (s, 2H), 6.12 (s, 2H),

A. Alam et al. / Tetrahedron 61 (2005) 1909–1918
1917
30 mg of desired 17 (30%). 1H NMR (CDCl3) d 2.04 (s, 3H),
3.85 (s, 3H), 5.08 (bs, 1H), 7.15 (d, 1H, JZ1.5 Hz), 7.28 (d,
1H, JZ1.8 Hz), 7.37–7.40 (m, 3H), 7.56–7.60 (m, 2H); 13C
NMR (CDCl3) d 27.07, 52.41, 107.73, 120.15, 123.42,
124.80, 129.25, 137.20, 140.01, 147.71, 165.70; GC-MS
m/z (%): 286 (M, 6), 271 (4), 255 (2), 184 (16), 153 (14),
103 (100).
5.12 (s, 2H), 7.34–7.45 (m, 6H); 13C NMR (CDCl3) d 13.32,
14.16, 42.24, 42.53, 52.40, 61.00, 71.25, 110.31, 113.93,
126.38, 127.45, 128.21, 128.51, 128.61, 135.96, 143.75,
146.29, 150.94, 152.57, 165.82. Anal. Calcd for
C21H24BrNO6: C, 54.09; H, 5.19; N, 3.00. Found: C,
54.20; H, 5.18; N, 3.08.
3.7. General procedure for the Ullmann coupling
3.6.9. Methyl 3-hydroxy-4,5-(diphenylmethylenedioxy)-
benzoate (19). Using the same procedure as of 12b,
compound 19 was obtained in 62% from commercially
available 2. IR (ATR): 3384, 1697, 1517, 1440, 1385, 1328,
1259, 1212, 1074, 1015, 781, 765, 707, 697 cmK1; 1H NMR
(CDCl3) d 3.85 (s, 3H), 5.61 (bs, 1H), 7.22 (d, 1H, JZ
1.5 Hz), 7.32 (q, 1H, JZ1.5 Hz), 7.35–7.40 (m, 6H), 7.53–
7.58 (m, 4H); 13C NMR (CDCl3) d 52.25, 103.27, 114.12,
118.72, 124.16, 126.27, 128.29, 129.37, 138.19, 139.06,
139.44, 148.33, 166.87; GC-MS m/z (%): 348 (M, 13), 317
(1), 271 (46), 211 (9), 165 (30), 105 (100), 77 (45).
To the mixture of bromo derivatives 11a or 14b and equal
amount (by weight) of activated Cu in dry DMF (0.5 ml/
mmol) was added and the resulted thick slurry was heated
for 3 h at 110 8C with stirring. Then, another 3 ml/mmol of
DMF was added and the mixture was heated at 180–185 8C
for 16–18 h. After cooling at around 100 8C, the reaction
mixture was poured into ice crushed and extracted with
CHCl3, dried over MgSO4. The highly florescent desired
coupling product was purified by silica gel column
chromatography eluted with 30–40% CHCl3 in hexane.
3.7.1. 4,40-Dimethoxy-5,6,50,60-dimethylenedioxy-2,20-
dimethoxycarbonylbiphenyl (a-DDB) (26). Using the
general procedure in Section 3.7, compound 26 was
obtained in 85% yield from 11a as a slight yellow solid;
mp 145–147 8C; IR(ATR): 1719, 1633, 1430, 1320, 1194,
3.6.10. Methyl 2-bromo-3-methoxy-4,5-di-hydroxy-
benzoate (21). Refluxing of 67 mg (0.13 mmol) of 20, in
AcOH/H2O (1:1, 1.5 ml) for 4 h yielded 38 mg (90%) of 21.
Similarly, refluxing of 46 mg (0.09 mmol) of 20 with 15 mg
of Amberlyst 15E in MeOH (1 ml) for overnight yielded
29 mg (100%) of 21 as a crystalline solid; mp 63–65 8C; IR
(ATR): 3530, 3230, 1694, 1589, 1514, 1431, 1364, 1313,
1253, 1209, 1062, 1022, 913, 774 cmK1; 1H NMR (CDCl3)
d 3.89 (s, 3H), 3.93 (s, 3H), 5.48 (s, 1H), 6.04 (s, 1H), 7.32
(s, 1H); 13C NMR (CDCl3–CD3OD) d 52.15, 60.44, 107.86,
114.28, 122.24, 142.34, 144.39, 145.46, 166.76; GC-MS
m/z (%): 278 (M, 45), 276 (M, 46), 263 (33), 261 (25), 257
(29), 105 (100). Anal. Calcd for C9H9BrO5: C, 39.01; H,
3.27. Found: C, 39.11; H, 3.10.
1
1173, 1100, 1040 cmK1; H NMR (CDCl3) d 3.67 (s, 6H),
3.96 (s, 6H), 5.99 (s, 4H), 7.38 (s, 2H); 13C NMR (CDCl3) d
51.85, 56.48, 102.28, 110.90, 112.21, 123.40, 138.10,
142.36, 147.07, 166.32. Anal. Calcd for C20H18O10. C,
57.42; H, 4.34. Found: C, 57.34; H, 4.43.
3.7.2. 6,60-Dimethoxy-4,5,40,50-dimethylenedioxy-2,20-
dimethoxycarbonylbiphenyl (b-DDB) (27). Using the
general procedure in Section 3.7, compound 27 was
obtained in 65% yield from 14b as a slight yellow solid;
mp 199–201 8C (lit.7a 207 8C); IR (ATR): 1720, 1618, 1477,
3.6.11. Methyl 3-diethylcarbamoyloxy-4-methoxy-5-ben-
zyloxybenzoate (24). A mixture of 22 (3.49 g, 12.1 mmol),
NaH (1.5 equiv), diethylcarbamoyl chloride (1.5 equiv) and
DMAP (cat.) in THF (65 ml) was refluxed for 2 h under the
nitrogen atmosphere. Removal of the solvent followed by
usual workup provided 4.52 g (100%) of crude 24, which
was almost pure and was used in the next step without
further purification. A portion of 200 mg was purified for the
analytical purpose. White crystalline solid; mp 95–97 8C; IR
1433, 1364, 1282, 1220, 1084, 1040 cmK1 1H NMR
:
(CDCl3) d 3.62 (s, 6H), 3.78 (s, 6H), 6.06 (s, 4H), 7.24 (s,
2H); 13C NMR (CDCl3) d 51.76, 59.71, 101.85, 104.81,
123.55, 127.20, 140.27, 140.95, 148.24, 166.28. Anal. Calcd
for C20H18O10. C, 57.42; H, 4.34. Found: C, 57.21; H, 4.12.
Acknowledgements
(ATR): 1714, 1412, 1333, 1260, 1155, 1081, 992, 750 cmK1
;
1H NMR (CDCl3) d 1.19 (t, 3H, JZ7.1 Hz), 1.28 (t, 3H, JZ
7.1 Hz), 3.38 (q, 2H, JZ7.1 Hz), 3.52 (q, 2H, JZ7.1 Hz),
3.87 (s, 3H), 3.92 (s, 3H), 5.15 (s, 2H), 7.33–7.45 (m, 5H),
7.47 (d, 1H, JZ1.8 Hz), 7.56 (d, 1H, JZ2.1 Hz); 13C NMR
(CDCl3) d 13.18, 14.03, 42.23, 42.53, 52.13, 60.76, 71.10,
112.35, 117.95, 124.80, 127.44, 128.06, 128.55, 136.32,
144.61, 146.17, 152.21, 153.77, 166.12; GC-MS m/z (%):
387 (M, 0.5), 357 (0.2), 100 (100), 91 (25), 72 (37). Anal.
Calcd for C21H25NO6: C, 65.10; H, 6.50; N, 3.62. Found: C,
65.09; H, 6.61; N, 3.61.
The author (A.A.) greatly acknowledges the cordial help of
Dr. Hideki Okamoto (Faculty of Science) and Mr. Takuzo
Komiyama (Faculty of Environmental Science and
Technology) of Okayama University.
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