Efficient synthesis of γ-DDB

Article abstract of DOI:10.1016/j.bmcl.2004.02.055

Synthesis of γ-DDB, which is another family member of α-DDB (dimethyl 4,4^′-dimethoxy-5,6,5^′,6 ^′- dimethylenedioxybiphenyl-2,2^′- dicarboxylate), is described. The unsymmetric isomer (γ-DDB) was constructed by a linker-directed intramolecular Ullmann coupling reaction, followed by the cleavage of the linker and re-esterification.

Full text of DOI:10.1016/j.bmcl.2004.02.055

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2131–2136
Efficient synthesis of c-DDB
c
b
b
b
Junbiao Chang,a,b, Xiaohe Guo, Senxiang Cheng, Ruiyun Guo, Rongfeng Chen
*
and Kang Zhaoa,*
aCollege of Pharmaceuticals and Biotechnology, Tianjin University, Tianjin 300072, PR China
bHenan Institute of Chemistry, Zhengzhou 450002, PR China
cChemistry Department, University of Science and Technology of China, Hefei, PR China
Received 24 December 2003; revised 6 February 2004; accepted 9 February 2004
Abstract—Synthesis of c-DDB, which is another family member of a-DDB (dimethyl 4,40-dimethoxy-5,6,50,60-dimethylene-
dioxybiphenyl-2,20-dicarboxylate), is described. The unsymmetric isomer (c-DDB) was constructed by a linker-directed intramo-
lecular Ullmann coupling reaction, followed by the cleavage of the linker and re-esterification.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
4,40-dimethoxy-5,6,50,60-dimethylene dioxybiphenyl-2,20-
dicarboxylate) and b-DDB, have been synthesized for
their conversion to the corresponding natural products
and other analogs. The preparation of those compounds
can be achieved by symmetrically coupling two
bromobenzene derivatives and some of the resulted
analogs have shown interesting biological activities as
antihepatotoxic and anticancer agents.10–18 Similarly, it
Schisandrin-type lignans, which are predominantly iso-
lated from schisandraceae, have the structural feature of
dibenzocyclooctandiene.1–9 The benzene rings of these
compounds are normally substituted with six alkoxy
groups as shown in compounds (A) and (B) (Fig. 1). The
corresponding acyclic compounds: a-DDB (dimethyl-
O
O
OR'
OMe
O
O
RO
O
O
O
MeO
O
CO2Me
CO2Me
MeO
MeO
CO2Me
CO2Me
MeO
MeO
CO2Me
CO2Me
X
O
RO
O
O
OMe
γ-DDB
O
OR'
OMe
A: R, R'=CH2, X=H
B: R=R'=Me, X=OH
β-DDB
α-DDB
OMe
O
O
O
O
CO2Me MeO
CO2Me
Br
Br
C
D
Figure 1.
Keywords: c-DDB; Ullmann; Unsymmetrical.
* Corresponding authors. Tel.: +86-2227405160; fax: +86-2227890968; e-mail: kz2@columbia.edu
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.02.055

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J. Chang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2131–2136
OH
OH
OH
Na2B4O7
Me2SO4
CH2I2
HO
OH
HO
OH
HO
OMe
K2CO3
MeOH
H2SO4
H2SO4
MeCOMe
CO2H
CO2CH3
CO2CH3
2
3
1
CO2Me
CO2Me
COCl
Br
O
Br
Br2
1) KOH
CHCl3
62%
2) SOCl2
3) 77%
OMe
OMe
OMe
O
O
5
O
O
O
6
4
HNO3
77%
CO2Me
Br
CO2Me
NO2
CO2Me
NH2
SnCl2
NaNO2/HCl
CuBr-HBr
Conc. HCl
34%
OMe
OMe
OMe
O
O
O
O
O
69%
9a
O
8
O
O
7
1) KOH
2) SOCl2 40%
HI
HNO2 50%
COCl
COCl
CO2Me
I
Br
I
1) KOH
OMe
OMe
2) SOCl2
3) 46.9%
OMe
9b
O
O
O
O
10a
10b
Scheme 1.
can be assumed that asymmetrical structure c-DDB is a
desirable starting material to be converted to the related
analogs for their biological studies. We report here a
synthetic procedure for preparing c-DDB by using the
key step of a salicylic alcohol-directed intramolecular
Ullmann coupling reaction.
It can be observed from the symmetric structures of
a-DDB and b-DDB that methyl 2-bromo-3,4-methylene-
dioxy-5-methoxybenzoate (C) can react with copper via
the Ullmann coupling reaction to give a-DDB, and
methyl 2-bromo-3-methoxy-4,5-methylenedioxybenzo-
ate (D) can give b-DDB. The corresponding intermo-
lecular Ullmann coupling reactions of the above
mentioned two bromides (C) and (D) in one reaction
process could not give c-DDB cleanly, but produce a
mixture of three DDB compounds (a-, b-, and c-iso-
mers). It is, however, hoped that a linker can be used to
connect two different phenyl bromides together, and
intramolecular coupling reaction shall give the unsym-
metrical compound such as c-DDB.
Figure 2.
Compound 4, which was prepared in three steps from
myristicinic acid 4, was easily brominated to compound
514 and then converted to the desired chloride 6. Alterna-
tively, the nitration of compound 4 proceeded smoothly to
give compound 7, which was reduced to 6-amino deriva-
tive 8. The Sandmeyer reactions of 8 gave bromo-deriva-
tive (9a mp 86.5 ꢁC) and iodo-derivative (9b mp 89 ꢁC),
which were converted to the corresponding halides 10a
and 10b, respectively. Since NMR spectroscopic data of
bromides 5 and 9a are very similar in terms of patterns and
chemical shifts, the compound identities have been inves-
tigated. Firstly, the 1H NMR spectroscopy of the mixture
of compounds 5 and 9a with the ratio of 2:1 presented two
sets of hydrogen atoms with the integration ratio of 2:1,
confirming compounds 5 and 9a to be different. Secondly,
the intermolecular Ullmann coupling reaction of 9a pro-
ceeded smoothly to give the corresponding b-DDB and the
1H NMR data of b-DDB is consistent with those reported
in the literature (Scheme 1).14
The Ullmann coupling reactions of diester 13a (Fig. 2)
proceeded in the presence of activated copper powder in
DMF after refluxing for 3h to result in the formation of 14.
By using 10b instead of 10a, the same diester 14 was pro-
duced in slightly improved yield and the structure of cou-

J. Chang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2131–2136
2133
O
O
O
O
DMAP
Et3N
DMAP
O
O
HO
HO
+
6/Et3N
MeO
O
MeO
60%
Cl
X
X
HO
10a: X=Br
10b: X=I
12a: X=Br
11
12b: X=I
O
O
O
O
O
O
O
O
MeO
COOH
COOH
MeO
O
O
KOH
Cu/DMF
MeO
O
O
O
O
X
Br
O
Reflux
25%
94.3%
O
O
O
O
O
15
OMe
13a: X=Br
13b: X=I
14
OMe
OMe
O
O
MeOH/H+
75%
MeO
CO2Me
CO2Me
O
O
16
OMe
Scheme 2.
pling product 14 was confirmed by high resolution MS and
1H NMR. The intramolecular coupling product 14 was
hydrolyzed by KOH solution to afford c-dicarboxylic acid
15. The desired c-DDB 16 was obtained by acid-catalyzed
esterification of compound 15 in MeOH (Scheme 2).
5 h. The solution was cooled to room temperature and
acidified with concentrated hydrochloric acid to pH 2 to
provide white powder. Then the powder was collected
and dried (4.27, 90%, mp 240–242 ꢁC). To the obtained
acid (4 g, 14.5 mmol) was added thionyl chloride (15 mL).
The mixture was heated to reflux for 4 h and was cooled
to room temperature to provide solid materials. The
SOCl2 solution was partially removed under reduced
pressure to provide more solid materials. The combined
solid materials were washed with cyclohexane to give
compound 6 (3.3 g, 77%), 146–148 ꢁC. MS (m=z, %), 294
(Mþ, 24), 257 (Mþ–Cl, 90), 77 (C6H5, 100).
2. Experimental section
The melting point (mp) was taken on XT-4 microscope
an uncorrected. IR was recorded on Perkin–Elmer 683
infrared spectrometer. H NMR data were obtained on a
Bruker DPX-400 spectrometer. Mass spectra was
recorded on a ZAB-HS mass spectrometer.
2.3. Methyl 3,4-dimethylenedioxy-5-methoxy-6-nitro-
benzoate (7)
2.1. Methyl 2-bromo-3,4-dimethylenedioxy-5-methoxy
benzoate (5)
To concentrated HNO3 (100 mL, d ¼ 1.45, 65%,
1.5 mmol) was added compound 4 (10 g, 47.6 mmol)
within 1 h at 5 ꢁC. The mixture was stirred for 1 h at 0 ꢁC
and was poured into the crushed ice (400 g) to provide
yellow solid materials. The solid materials were filtered,
washed with water, and dried to give crude products
(11.2 g). The crude products were recrystallized
from ethyl acetate to give compound 7 (9.4 g, 77%),
mp 124–126 ꢁC (Ref. 14 126–128 ꢁC). 1H NMR (CDCl3)
d 7.241 (s, 1H, ArH), 6.242 (s, 2H, OCH2O), 4.175
(s, 3H, OCH3), 3.969 (s, 3H, COOCH3).
To the solution of methyl 3,4-dimethylenedioxy-5-
methoxy benzoate (22 g, 0.105 mmol) in acetic acid
(130 ml) was added dropwise the mixture of bromine
(16.8 g, 0.21 mmol) in acetic acid (60 mL) at low tem-
perature (12–15 ꢁC). The resulting solution was stirred
for 2 h at room temperature and was poured into ice
water to provide solid materials. Then the solid mate-
rials were filtered, washed with water, and dried over
MgSO4 to give crude products (28 g), which were
recrystallized from ethanol twice to give compound 5
(19 g, 62%), mp 104–106 ꢁC (reference value19) 106.5 ꢁC.
2.4. Methyl 6-amino-3,4-dimethylenedioxy-5-methoxy
benzoate (8)
2.2. 2-Bromo-3,4-dimethylenedioxy-5-methoxy benzoic
acid chloride (6)
To SnCl2Æ2H2O (5 g, 22 mmol) was added concentrated
hydrochloric acid (50 mL). The mixture was heated to
melt completely and compound 7 (5 g, 19.6 mmol) was
To compound 5 (5 g, 18.1 mmol) was added KOH solu-
tion (150 mL, 5%). The mixture was heated to reflux for

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J. Chang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2131–2136
then added at 40 ꢁC. The nitro-compound was heated
to reflux for 0.5 h and cooled to room temperature.
The solvent was removed to provide solid materials,
which was neutralized with NaOH solution (10%)
to provide white solid materials. The white solid
materials were mostly dissolved in cyclohexane and
filtered. Filtrate solution precipitates compound 8 (1.5 g,
34%), mp 88–90 ꢁC (Ref. 14 90–91 ꢁC). 1H NMR
for 5 h and was added concentrated hydrochloric acid
(pH ¼ 2) to give powder, which was filtrated to give 6-
bromo-3,4-dimethylenedioxy-5-methoxy benzoic acid
(1.55 g, 81%), mp 188–190 ꢁC. IR (cc¼0, 1700 cmÀ1). To
this acid (2 g, 7.27 mmol) was added thionyl chloride
(6 mL). The mixture was stirred for 5 h at 50 ꢁC. Re-
moval of thionyl chloride under reduced pressure gave
yellow solid materials, which were filtered to give com-
pound 10a (0.86 g, 40%), mp 136–138 ꢁC. IR (cc¼0
1750 cmÀ1).
(CDCl3) d 7.01 (s, 1H, ArH), 5.883(s, 2H, OCH O),
2
3.99 (s, 3H, OCH3), 3.82 (s, 3H, COOCH3), 5.0 (br, 2H,
ArNH2).
2.8. 6-Iodo-3,4-dimethylenedioxy-5-methoxy benzoyl
chloride (10b)
2.5. Methyl 6-bromo-3,4-dimethylenedioxy-5-methoxy
benzoate (9a)
To compound 9b (1 g, 3mmol) was added KOH (30 mL,
5%). The mixture was refluxed for 4 h. The solution was
acidified with concentrated HCl to give white powder.
The powder was filtered and dried to provide 6-iodo-3,4-
dimethylenedioxy-5-methoxy benzoic acid (0.8 g, 88%),
mp 178–180 ꢁC, IR (cc¼0 1700 cmÀ1). To this acid (0.8 g,
2.38 mmol) was added thionyl chloride (2.8 mL). The
mixture was stirred for 5.5 h at 50 ꢁC. Removal of
thionyl chloride under reduced pressure gave compound
10b (0.38 g, 46.9%), mp 145–147 ꢁC. IR (cc¼0 1752 cmÀ1).
To CuSO4Æ5H2O (2 g, 8 mmol) were added potassium
bromide(1 g, 8.4 mmol) and water (10 mL). After heat-
ing the mixture to become melted, NaOH solution
(0.6 g, 15 mmol) and NaHSO3 solution (0.6 g, 5.7 mmol)
were sequentially added. The resulting solution was
stirred to provide CuBr, which was washed with water
three times and mixed with hydrobromic acid (5 mL,
40%) for the next step.
To compound 8 (1 g, 4.44 mmol) in hydrobromic acid
(5 mL, 40%), was added dropwise sodium nitrite solution
(0.5 g, 10.6 mmol) in 2.5 mL water at 0–5 ꢁC until KI-
starch paper showed light purple. The resulting solution
was poured into a suspension of CuBr. Upon standing
overnight, materials were extracted with benzene, wa-
shed with NaHCO3 solution (10%), and dried with
anhydrous CaCl2 to provide crude products (0.9 g). The
crude products were recrystallized from ethanol to give
compound 9a (0.89 g, 69%), mp 80–82 ꢁC (Ref. 14 82–
2.9. Salicylalcohol diester (13a)
To dried DMF (20 mL) were added salicylalcohol
(100 mg, 0.8 mmol), triethylamine (1 mL), DMAP, and
compound 10a (236 mg) at À20 ꢀ À30ꢁC. The mixture
was stirred for 1 h at À20 ꢀ À30ꢁC and another 6 h at
room temperature. Compound 6 was then added at
À20 ꢀ À30ꢁC and stirred for 0.5 h at this temperature
and for additional 12 h at rt. The solution was poured
into water to provide solid. The solid materials were
mixed with ethyl acetate, which was washed with brine.
The organic phase was dried over anhydrous magne-
sium sulfate. After filtration, removal of solvents gave
solid materials, which was recrystallized from chloro-
form–methanol to give compound 13a (0.34 g, 60%), mp
160–162 ꢁC. Anal. Calcd for C25H18O10Br2C: 47.03, H:
1
83 ꢁC). H NMR (CDCl3) d 7.03(s, 1H, ArH), 6.07 (s,
2H, OCH2O), 4.04 (s, 3H, OCH3), 3.90 (s, 3H, CO-
OCH3), MS (m=z, %) 288 (Mþ, 30), 257 (M–OCH3, 87).
2.6. Methyl 6-iodo-3,4-dimethylenedioxy-5-methoxy
benzoate (9b)
þ
To compound 8 (6 g, 26 mmol) was added concentrated
hydrochloric acid (5 mL). To the mixture was added
dropwise sodium nitrite solution at 0–5 ꢁC until KI-
starch paper showed purple. The resulting solution was
added KI solution to provide black solid materials.
After extracting with benzene, the solution was washed
with NaOH solution twice, and with brine once. The
benzene solution was then dried over anhydrous CaCl2
to provide crude products. The crude products were
recrystallized from anhydrous ethanol to give com-
pound 9b (0.5 g, 50%), MS (m=z, %), 336 (Mþ, 100), 305
(Mþ–OCH3, 77).
2.84; found C: 47.18, H: 2.70. MS (m=z, %) 63 8 (M , 6),
558 (Mþ–Br, 1), 259 (C9H6O4Brþ, 100), 179 (C9H6O4
22). H NMR (DMSO-d6) d ppm 7.63(d, 1H, ArH),
7.51 (m, 1H, ArH), 7.53(s, 1H, ArH), 7.36 (m, 2H,
ArH), 6.85 (s, 1H, ArH), 6.237 (s, 2H, OCH2O), 6.13(s,
,
þ
1
2H, OCH2O), 5.31 (s, 2H, ArCH2), 3.91 (s, 3H,
ArOCH3), 3.86 (s, 3H, ArOCH3).
X-ray structural determination crystal data compound
ꢀ
13a:
C25H18O10Br2
ꢀ
M ¼ 638:22
A ¼ 9:442(4) A
ꢀ
B ¼ 29:93(1) A C ¼ 8:869(3) A b ¼ 100:21(2) ꢁV ¼
3
ꢀ
2467ð1Þ A primitive monoclinic cell P21/C(#14) Z ¼ 4
Dx ¼ 1:72 g/cm3
lðMoKaÞ ¼ 33:53cm À1
F(000)
1272.00. The diffraction experiment was carried out
using a colorless transparent prisma with dimension of
0.60 · 0.40 · 0.30 mm. The diffractometer RAX1S-IV
was used with graphite monochromated MoKa radia-
tion (k ¼ 0:71070 nm). The structure was solved by a
direct method using teXsan and Fourier method. The
2.7. 6-Bromo-3,4-dimethylenedioxy-5-methoxy benzoyl
chloride (10a)
To compound 9a (2 g, 6.92 mmol) was added KOH
solution (50 mL, 5%). The mixture was heated to reflux

J. Chang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2131–2136
2135
refinement of atomic parameters was carried out using
full-matrix least-squares methods with anisotropic tem-
perature factors. Throughout the refinement, the func-
1H NMR (Acetone-d6) ppm 7.25 (s, 1H, ArH), 7.11 (s,
1H, ArH), 6.00 (d, 2H, OCH2), 5.82 (d, 2H, OCH2O),
3.82 (s, 3H, OCH3).
2
tion RwðjFoj À jFcjÞ was minimized. The weighting
scheme of w ¼ 1=r2ðFoÞ was used during the final
refinement stage. The final R value is 0.054 (Rw ¼ 0:077).
Atomic coordinates and esd ꢀs have been deposited at
the Cambridge Crystallographic Data Center.
2.13. Dimethyl 7,40-dimethyl-[4,50]bi[1,3-benzodioxolyl]-
5,6-dicarboxylate(r-DDB, 16)
A mixture of 15 (50 mg, 0.13mmol), CH 3OH (10 mL)
and Concd H2SO4 (0.1 mL) was refluxed for 5 h under
vigorous stirring. The mixture was poured into ice-water
and extracted with AcOEt. The solvent was evaporated
to provide 40 mg (75%) of 16. Mp 150–152 ꢁC. Anal.
Calcd for C20H18O10: C, 57.42; H, 4.34 Found: C, 57.32;
2.10. Salicylalcohol diester (13b)
To dried DMF (20 mL) were added salicylalcohol
(100 mg, 0.8 mmol), triethylamine (1 mL), DMAP, and
compound 10b (236 mg) at À20 ꢀ À30ꢁC. The mixture
was stirred for 1 h at À20 ꢀ À30ꢁC and another 6 h at
room temperature. Compound 6 was then added at
À20 ꢀ À30ꢁC and stirred for 0.5 h at this temperature
for additional 12 h at rt. The solution was poured into
water to provide solid, which was mixed with ethyl
acetate. After the ethyl acetate was washed with brine,
the organic phase was dried over anhydrous magnesium
sulfate. Removal of solvents gave solid materials, which
were recrystallized from chloroform–methanol to give
1
H, 4.43. H NMR (CDCl3). d ppm 7.16 (s, 1H, ArH),
7.35 (s, 1H, ArH), 5.97 (s, 2H, –OCH2O–), 6.14 (s, 2H,
–OCH2O–), 3.57 (s, 3H, –OCH3), 3.59 (s, 3H, –OCH3),
3.76 (s, 3H, ArOCH3), 3.96 (s, 3H, ArOCH3).
Acknowledgements
K.Z. acknowledges the Outstanding Young Scholarship
from NSFC (#30125043), the Basic Research Project
(#2002CCA01500) of the MOST and the Cheung Kong
Scholars Programme for the financial supports.
1
compound 13b (0.35 g, 60%), mp 160–162 ꢁC. H NMR
(Acetone-d6) d ppm 7.66 (d, 1H, ArH), 7.50 (t, 1H,
ArH), 7.35 (m, 2H, ArH), 7.573(s, 1H, ArH), 6.913(s,
1H, ArH), 6.13(s, 2H, OCH O), 6.22 (s, 2H, OCH2O),
2
5.37 (s, 2H, ArCH2), 3.93 (s, 3H, ArOCH3), 3.94 (s, 3H,
ArOCH3).
References and notes
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2
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under vigorous stirring. The solvent was evaporated
under reduced pressure and then acidified to pH 1 by
dropwise adding 10% HCl. The mixture was extracted
with AcOEt. The solvent was evaporated to provide
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C18H14O10: C, 55.39; H, 3.62. Found: C, 55.28; H, 3.70.

2136
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