Anodic Oxidation of Mono- and Disubstituted 1,4-Dimethoxybenzenes

Article abstract of DOI:10.1021/jo0302253

The electrochemical oxidation of mono- and disubstituted 1,4-dimethoxybenzene derivatives with zero, one, and two benzylic CH2X groups (X = OAc, Cl, OH) (5a-c and 6a-c) has been carried out by using both constant-current and controlled-potential techniques in methanol and in the presence of different electrolytes and working electrodes. Constant-current electrolysis in KOH-methanol solutions yielded mostly the corresponding 1,4-quinone derivatives from 5a-c and 6b, whereas the disubstituted 1,4-dimethoxybenzenes 6a,c underwent side-chain oxidation to form 2,5-dimethoxyterephthalaldehydes. Upon alteration of the medium from the commonly used basic KOH-methanol to neutral LiClO₄-methanol, a new spectrum of products was achieved in most cases, involving novel coupling products from monosubstituted substrates and quinone derivatives from disubstituted ones. Controlled-potential oxidation at the glassy carbon anodes and in a neutral LiClO₄-methanol medium led to more complex mixtures of products, namely, polymers and new coupling products from monosubstituted substrates and quinones and side-chain oxidation (or substitution) products from the disubstituted ones. Three new coupling products were isolated and characterized by X-ray measurements.

Full text of DOI:10.1021/jo0302253

An od ic Oxid a tion of Mon o- a n d Disu bstitu ted
1,4-Dim eth oxyben zen es
Cheng-Chu Zeng and J ames Y. Becker*
Department of Chemistry, Ben-Gurion University, Beer-Sheva 84105, Israel
becker@bgumail.bgu.ac.il
Received J uly 14, 2003
The electrochemical oxidation of mono- and disubstituted 1,4-dimethoxybenzene derivatives with
zero, one, and two benzylic CH2X groups (X ) OAc, Cl, OH) (5a -c and 6a -c) has been carried out
by using both constant-current and controlled-potential techniques in methanol and in the presence
of different electrolytes and working electrodes. Constant-current electrolysis in KOH-methanol
solutions yielded mostly the corresponding 1,4-quinone derivatives from 5a -c and 6b, whereas
the disubstituted 1,4-dimethoxybenzenes 6a ,c underwent side-chain oxidation to form 2,5-
dimethoxyterephthalaldehydes. Upon alteration of the medium from the commonly used basic
KOH-methanol to neutral LiClO4-methanol, a new spectrum of products was achieved in most
cases, involving novel coupling products from monosubstituted substrates and quinone derivatives
from disubstituted ones. Controlled-potential oxidation at the glassy carbon anodes and in a neutral
LiClO4-methanol medium led to more complex mixtures of products, namely, polymers and new
coupling products from monosubstituted substrates and quinones and side-chain oxidation (or
substitution) products from the disubstituted ones. Three new coupling products were isolated and
characterized by X-ray measurements.
In tr od u ction
The oxidation of 1,2-, 1,3-, and 1,4-dimethoxybenzenes
was studied electrochemically1,2 in MeOH-KOH solu-
tions and was shown to yield mainly the bisketals of
benzoquinones 1, 2, and 3, respectively:
tems.5 By variation of the substitution pattern or reaction
medium (solvent, electrolyte), different pathways were
shown to exist, e.g., the formation of bisaryl derivatives
from the anodic oxidation of 1,2,4-trimethoxybenzene,6
triarylene from 1,2-dimethoxybenzene in TFA,7 and p-
methoxybenzonitrile and cyanotrimethoxycyclohexa-
diene from 1,4-dimethoxybenzene, in the presence of
NaCN.8
Hydrolysis of substituted 3 has been demonstrated3 to
take place regioselectively to provide synthetically useful
dienones 4. Such quinono monoketals have found exten-
sive use in organic synthesis.4
Later, the electrochemical oxidation was extended to
the more functionalized 1,4-dimethoxy-aromatic sys-
Electrochemical studies of di-, tri-, and tetrasubstituted
1,4-dimethoxybenzenes are limited.2,9 Moreover, most of
(1) (a) Bellaeau, B.; Weinberg, N. L. J . Am. Chem. Soc. 1963, 85,
2524. (b) Bellaeau, B.; Weinberg, N. L. Tetrahedron 1973, 29, 279.
Bellaeau, B.; Weinberg, N. L. In Chemistry of quinones; Rappoport,
Z., Patai, S., Eds.; J ohn Wiley: New York, 1988; Part 2, p 899.
(2) Swenton, J . S. Acc. Chem. Res. 1983, 16, 74.
(3) (a) Henton, D. R.; McCreery, R. L.; Swenton, J . S. J . Org. Chem.
1980, 45, 369. (b) Henton, D. R.; Chenard, B. L.; Swenton, J . S. J .
Chem. Soc., Chem. Commun. 1979, 326. (c) Gautier, E. C. L.; Lewis,
N. J .; McKillop, A.; Taylor, R. J . K. Synth. Commun. 1994, 24, 2989.
(d) Irngartinger, H.; Stadler, B. Eur. J . Org. Chem. 1998, 605.
(4) Swenton, J . S. In Electroorganic synthesis (festschrift for Manuel
M. Baizer); Little, R. D., Weinberg, N. L., Eds.; Marcel Dekker: New
York, 1991 (see refs 7 and 8 on p 151).
(5) (a) Chenard, B. L.; McConnel, J . R.; Swenton, J . S. J . Org. Chem.
1983, 48, 4312. (b) Swenton, J . S.; Freskos, N. J .; Monrow, G. W.
Tetrahedron 1984, 40, 4625.
(6) Grimshaw, J . Electrochemical reaction and mechanisms in
organic chemistry; Elsevier: London, 2000; p 201.
(7) Bechgaard, K.; Parker, V. D. J . Am. Chem. Soc. 1972, 94, 4749.
(8) (a) Andreas, S.; Zahnow, E. W. J . Am. Chem. Soc. 1969, 91, 4181.
(b) Eberson, L.; Helgee, B. Acta Chem. Scand., Ser. B 1975, 29, 451.
(c) Weinberg, N. L.; Marr, D. H.; Wu, C. N. J . Am. Chem. Soc. 1975,
97, 1499.
(9) (a) Irngartinger, H.; Stadler, B. Eur. J . Org. Chem. 1998, 595.
(b) Parker, V. D. J . Chem. Soc., Chem. Commun. 1969, 610.
10.1021/jo0302253 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004
J . Org. Chem. 2004, 69, 1053-1059
1053

Zeng and Becker
from 1,4-dimethoxybenzene (5a ) and dienone 4 from 2.3
Electrolysis of the monosubstituted derivatives 5b,c,
followed by hydrolysis in acetone-sulfuric acid, yielded
quinone derivatives of type 7 as the major products (all
quoted yields are of the isolated products after column
chromatography and purification, based on 2 mmol
(∼300-500 mg) of starting material). However, when the
TABLE 1. An od ic P ea k P oten tia ls a n d Ap p lied
P oten tia ls for th e P r ep a r a tive Electr olysis
peak potentials
at Pta
peak potentials
at GCb
applied
potentials
substrates E11/2 (ox)d
E2ox
E1ox
E2ox
at GC anodec
5a
5b
5c
6a
6b
6c
1.25
1.27
1.19
1.24
1.34
1.13
1.57e
1.83
1.36f
1.82
1.90
1.67
1.29
1.32
1.23
1.31
1.36
1.16
1.74
1.67
1.34g
1.68
1.69
1.45h
1.08
1.10
1.00
1.10
1.15
1.00
a
Cyclic voltammetry measurements were carried out in 0.1 M
LiClO4/CH3CN; Pt working electrode; scan rate 100 mV/s. Refer-
ence electrode: Ag/AgCl (-0.045 V versus SCE). b In 0.1 M LiClO4/
CH3OH; GC working electrode; scan rate 100 mV/s. c Controlled-
potential electrolyses were done in 0.1 M LiClO4/CH3OH at a GC
working electrode; quasi-reference electrode ) a polished Ag wire.
All waves are reversible. e A third wave is observed at E3ox
)
d
disubstituted derivatives 6a -c were oxidized under the
same conditions, only 6b gave quinone 8, whereas the
other two substrates yielded a product in which the
oxidation took place at both side chains to generate the
bisaldehyde dimethoxybenzene 9 (major). The fact that
3
g
1.92 V. f A third wave is observed at Eox ) 1.75 V. A third wave
3
h
is observed at Eox ) 1.41 V (ill-defined). A third wave is
observed at E3ox ) 1.27 V (ill-defined).
the published papers on the anodic oxidation of dimeth-
oxyarenes are confined to constant-current electrolysis
in basic media. The present paper describes the anodic
oxidation of derivatives of mono- and disubstituted 1,4-
dimethoxybenzenes (types 5 and 6) in methanol by both
constant-current and controlled-potential techniques in
both basic and neutral electrolytes. The paper mostly led
to new types of products.
9 does not undergo further oxidation is not surprising,
because former attempts to oxidize 1,4-dimethoxyben-
zenes monosubstituted by a carbonyl functionality (al-
dehyde, ketone, or carboxylic group) have failed.3c
Resu lts a n d Discu ssion
1. Cyclic Volta m m etr y. Cyclic voltammetry mea-
surements of 5a -c and 6a -c in an acetonitrile-0.1 M
lithium perchlorate solution at a Pt working electrode
show that each substrate exhibits two oxidation waves,
the first being reversible and the second being irrevers-
ible. The first anodic potentials appear at 1.2-1.4 V
(versus Ag/AgCl), and the second anodic potentials ap-
pear at more positive potentials (1.4-1.9 V). When the
solvent is methanol, and the working electrode is a glassy
carbon (GC), the first oxidations become irreversible
(Table 1). Obviously, acetonitrile stabilizes the cation-
radical intermediates more efficiently than methanol.
All of the second oxidation waves (in both solvents) are
ill-defined, and their approximate potentials were de-
duced by square-wave voltammetry.
2. Con sta n t-Cu r r en t Electr olysis. To compare the
behavior of 1,4-dimethoxybenzenes 5b,c and 6a -c with
that found in the literature, we first carried out constant-
current electrolysis using the conditions described in the
literature, viz., at a Pt anode in MeOH-KOH,1 following
the experimental conditions of the well-known examples
of obtaining 1,1,4,4-tetramethoxy-2,5-cyclohexadiene (3)
Attempts to characterize products of constant-current
electrolyses of 5a -c in the absence of a base, by using a
neutral LiClO4 electrolyte instead, were only partially
successful. A polymer was formed from 5c, and the
complex mixtures of products (at least seven) were
formed from 5a and 5b. The two dimeric isomers 10a
(17%) and 10b (17%), in addition to dimer 11 (19%), were
isolated (before hydrolysis) from the reaction mixture of
5a , and quinone 12 (15%, with methoxy and methyl
substituents) was isolated from 5b. These results are
unprecedented (although in low yields) in comparison
with the outcome stemming from electrolysis in the
base-methanol solutions. Spectral data of the two iso-
mers 10a and 10b did not allow for a distinction between
them. Fortunately, we obtained good quality crystals for
both for X-ray measurements and succeeded in establish-
ing their structures (see the Supporting Information).
Product 11 contains a phenolic OH (disappears in its H1
NMR spectrum upon addition of D2O). It may serve as
the precursor of 10b. For instance, its keto form could
undergo further methoxylation to generate 10b. Product
12, bearing a methyl substituent at one of the vinylic
1054 J . Org. Chem., Vol. 69, No. 4, 2004

Mono- and Disubstituted 1,4-Dimethoxybenzenes
carbons, is known in the literature24 and gave an identical
H1 NMR spectrum and melting point. It is likely that the
C-Cl bond in the substrate 5b undergoes a homolytic
cleavage (e.g., assisted by a cation-radical intermediate),
followed by a H-atom abstraction to form 12.
acterized, it is quite sensitive to trace amounts of acid
and undergoes rapid hydrolysis to afford 18 (38%). We
1
were unable to obtain an X-ray structure for 17, but H
and 13C NMR data, elemental analysis, and HRMS point
to the suggested structure.
3. Con tr olled-P oten tial Electr olysis. The controlled-
potential oxidation of 5a and 5c in LiClO4-methanol at
a Pt anode led to the polymeric products. Therefore, we
elected to use a GC anode under these conditions. The
electrolyses of 5a -c and 6a -c have been found to be less
selective (in terms of the number of products) compared
with constant-current oxidation but usually afforded
different types of products. Also, the outcome has been
found to be sensitive to the nature of the substituents.
For instance, each of the 5a -c compounds behaved
differently. Whereas the unsubstituted 5a afforded a
complex mixture of products (at least five) from which
the dimer 19 (18%) was isolated and characterized by
its X-ray analysis (see the Supporting Information), 5b
and 5c yielded polymers under the same conditions.
The constant-current oxidation of the disubstituted
derivatives 6a -c in the presence of a neutral electrolyte
(LiClO4) was also found to be less selective than that
under basic conditions and generated complex mixtures
of five to eight products. Some of the products were
isolated and characterized, such as the expected quinone
8 (14%) from 6b, two quinonic derivatives [13 (13%) and
14 (6%)] and the monohydrolysis product 15 (39%) from
6a , and the products 16 (17%) and 17 (10%) from 6c. It
is noteworthy that, although 15 was isolated and char-
All of the disubstituted derivatives 6a -c gave mixtures
of products, of which we were able to characterize a few
of them. Two quinone products, 20 (14%) and 13 (13%),
were isolated from 6a . They are similar to 8 but with
substitution (20) or partial hydrolysis (13) at the side
chains. In addition, a hydroquinone (21 (22%), involving
oxidation at the side chain, was also detected. Derivative
6c also gave quinone 20 (18%), in addition to bisaldehyde
9 (13%). As for 6b, quinone 8 (17%) was isolated, in
addition to 22 (8%).
4. Mech a n ism . An ECEC (E ) electrochemical and C
) chemical step) type mechanism has been suggested10
for the formation of bisketals from 1,4-dimethoxybenzene
in methanol, as is described in Scheme 1. The outlined
mechanism involves an initial formation of a cation
(10) Nilsson, A.; Palmquist, U.; Pettersson, T.; Ronlan, J . J . Chem.
Soc., Perkin Trans. 1 1978, 708.
J . Org. Chem, Vol. 69, No. 4, 2004 1055

Zeng and Becker
SCHEME 1
SCHEME 2
radical followed by a nucleophilic attack of the solvent
(methanol) and loss of a proton to form a cyclic radical
species, which could then undergo an additional oxidation
at the anode and a further reaction with methanol to
yield a bisketal product.
ample, both p-methoxytoluene14 and 1-allyl-3,4-dimethoxy-
benzene (methyleugenol)15 undergo methoxylation at the
benzylic/allylic position under the appropriate conditions.
Primary benzylic alcohols are known to undergo anodic
oxidation in acetonitrile to afford the corresponding
aldehydes16 and acids.17,18
Using basic methanol solutions, one cannot rule out
the involvement of MeO• and/or MeO-) in the mechanism
outlined in Scheme 1. These species could react (in
parallel or in competition with methanol) with charged
and neutral species electrogenerated from the substrate
to yield mono- and bisketal derivatives. At least three
different pathways involving MeO- and MeO• species in
the nucleophilic/addition reactions are described in the
literature.11
Regarding the formation of the dimeric products from
methoxybenzenes, to the best of our knowledge, the only
known examples are confined to dehydrodimerization6,19
(e.g., from 1,2,4-trimethoxybenzene and 2,5-dimethoxy-
toluene) and dehydrocyclic trimerization7 (e.g., from 1,2-
dimethoxybenzene). Therefore, the formation of the
dimers 10a , 10b, 11, and 19 is unique not only because
of their structure but also because of the fact that they
are obtained from 1,4-dimethoxybenzene for the first
time. A plausible mechanism for their formation is
described in Scheme 2, assuming the dimerization of the
initially formed cation radical, followed by the methoxy-
lation at the para position to the carbon that undergoes
coupling and further oxidation and substitution. The
suggested mechanism in Scheme 2 is supported by the
isolation and identification of intermediate 10, which
could be a precursor of 19. Similarly, one could postulate
the formation of the coupled product 11 by assuming a
The yields of the products are invariably low, especially
when electrolysis takes place in the neutral solutions (no
attempts were made to optimize or scale up the amount
of substrate to larger quantities than ∼300-500 mg). It
seems that under these conditions, except for the solvent
methanol, there are no other nucleophiles (such as the
methoxy anion) to trap the electrogenerated cation
radicals (and facilitate deprotonation from the intermedi-
ates). Instead, there are competitive reactions of the
cation radicals and radical species (among themselves
and with the substrate) that lead to multiple products
and make the reaction less selective. This argument is
well supported by the case of anodic oxidation of a
tetrasubstituted compound 1,4-dimethoxydurane, which
shows high selectivity by affording no dimers but
duraquinone as the sole product.12
(11) Hammerich, O.; Svensmark, B. In Organic Electrochemistry,
3rd ed.; Lund, H., Baizer, M. M., Eds.; Marcel Dekker: New York, 1991;
Chapter 16, pp 631-2.
(12) Parker, V. D. J . Chem. Soc., Chem. Commun. 1969, 610.
(13) (a) Coleman, A. E.; Richtol, H. H.; Aikens, D. A. J . Electroanal.
Chem. 1968, 18, 165. (b) Svanholm, U.; Parker, V. D. J . Chem. Soc.,
Perkin Trans. 2 1976, 1567. (c) Brinkhaus, K. H.; Steckhan, E.; Degner,
D. Tetrahedron 1986, 42, 553.
(14) See: Reference 4, p 149. Dolson, M. G.; Swenton, J . S. J . Am.
Chem. Soc. 1981, 103, 2361.
(15) (a) Wang, S.; Swenton, J . S. Tetrahedron Lett. 1990, 31, 1513.
(b) Vargas, R. R.; Pardini, V. L.; Viertler, H. Tetrahedron Lett. 1989,
30, 4037.
The formation of monoketal dienones 4 and quinones
7 and 8 stems from the hydrolysis steps, depending on
the acidic conditions (acetone-AcOH and acetone-
H2SO4, respectively). Products of type 9 stem from
benzylic oxidation, a common process in anodic oxidation
of alkyl-arenes and para-substituted toluenes.13 Also, it
is known that side-chain oxidation of some methoxyben-
zenes competes favorably with ring oxidation. For ex-
(16) Lund, H. Acta Chem. Scand. 1957, 11, 491.
(17) Mayeda, E. A.; Miller, L. L.; Wolf, J . F. J . Am. Chem. Soc. 1972,
94, 6812.
(18) Bower, W. J .; Zuman, P. J . Electrochem. Soc. 1975, 122, 368.
(19) Parker, V. D.; Adams, R. N. Tetrahedron Lett. 1969, 10, 1721.
1056 J . Org. Chem., Vol. 69, No. 4, 2004

Mono- and Disubstituted 1,4-Dimethoxybenzenes
ing electrode was a platinum disk (ca. φ ) 1 mm) or GC disk
electrode (ca. φ ) 3 mm). The auxiliary and reference elec-
trodes in these studies were Pt and Ag/AgCl [in 2 M NaCl and
-0.045 V versus a saturated calomel electrode (SCE)], respec-
tively. A total of 0.1 M LiClO4 was used as the supporting
electrolyte in HPLC-grade acetonitrile or methanol as the
solvents at a scan rate of 100 mV/s. The concentrations of the
substrates were 1-2 M.
SCHEME 3
Controlled-potential electrolyses were conducted in an H-
type cell equipped with a medium glass frit as the membrane
used for preparative electrolysis. The anode compartment
contained a polished GC plate (∼4.5 cm2) as the anode and a
polished silver wire quasi-reference electrode, immersed in an
electrolyte solution in a glass cylinder with a fine glass frit at
its end. A stainless steel rod (φ ) ∼6 mm) as the counter
electrode is immersed in the cathode compartment. Typically,
the anodic compartment contained 2 mmol of substrates
dissolved in about 25 mL of a solvent-electrolyte solution, and
the whole cell is kept in water at room temperature. In a
typical experiment, 25 mL of a 0.1 M methanol solution of
lithium perchlorate was pre-electrolyzed at the chosen poten-
tial (see Table 1) in the H-type cell for 10 min. Subsequently,
2 mmol of substrates was added to the anode compartment.
The electrolysis was terminated when all of the substrate was
consumed (checked by TLC) or the current reached 5% of its
initial value. After electrolysis, the solvent was evaporated
under reduced pressure. The residue was dissolved in CHCl3
(40 mL) and washed with water (20 mL). The separated
organic layer was dried over MgSO4. After the evaporation of
the solvent, the crude product was purified by column chro-
matography on silica gel eluting with a mixture of petroleum
ether and ethyl acetate with a gradual increase of polarity to
give the products.
Constant-current electrolyses were conducted in a 50 mL
beaker-type cell (undivided) equipped with a platinum foil (3.5
cm2) anode and a stainless steel rod cathode, which were
connected to a direct-current generator. The cell contained 30
mL of solution, and the amount of substrate is 2 mmol. In a
typical experiment under neutral conditions, a platinum plate
(∼5 cm2) as the working electrode and a stainless steel rod as
the counter electrode were polished. In a beaker-type cell with
parallel arrangement of the cathode and anode, 2 mmol of
substrates was dissolved or suspended in 30 mL of a 0.1 M
LiClO4-methanol solution. The stirred solution or suspension
was electrolyzed at 200 mA for about 2 h and terminated when
all of the substrate was consumed (checked by TLC; electroly-
sis at 400 mA gave a lower yield). After electrolysis, the solvent
was evaporated under reduced pressure. The residue was
dissolved in CHCl3 (40 mL) and washed with water (20 mL).
The separated organic layer was dried over MgSO4. After the
evaporation of the solvent, the crude product was purified by
column chromatography on silica gel, eluting with a mixture
of petroleum ether and ethyl acetate with a general increase
of ethyl acetate to give the products.
dimethoxylation step (at the carbon positioned para to
the carbon that is coupled by the other benzene ring) after
the coupling between the two benzene moieties.
Oxidation at the side chain is not surprising because
it is known17 that benzylic alcohols, ethers, and esters
can undergo electrochemical oxidation in the presence
of LiClO4 to give carbonylic compounds (aldehyde, ketone,
and carboxylic acid). The formation of 20 from 6a and
6c could be explained by assuming a loss of carbon
dioxide from carboxylic acid, followed by electrochemical
ring oxidation to generate a cation radical. A positively
charged intermediate could then be trapped by methanol
to form product 20. A general mechanism, which il-
lustrates how a benzylic carbon could be replaced by a
methoxy group, is outlined in Scheme 3. Previously, we
observed partial hydrolysis at the benzylic side-chain
positions (see product 13). In the case of the hydro-
quinone 21, the hydrolysis of the methoxy groups that
are directly linked to the aromatic nucleus takes place.
It is reasonable to assume that in both cases hydrolysis
is promoted by the protons. As to the source of protons,
it has already been demonstrated by the various mecha-
nistic schemes in this paper how they could be released.
Con clu sion
Electrochemical oxidation of the mono- and disubsti-
tuted 1,4-dimethoxybenzene derivatives 5a -c and 6a -c
has been carried out using constant-current and controlled-
potential techniques and different electrolytes and work-
ing electrodes. According to the commonly used condi-
tions (2% KOH/MeOH, constant current, and platinum
anode), quinone derivatives were produced after the
hydrolysis of the corresponding quinone bisketals from
all monosubstituted (5a -c) and disubstituted (6b) de-
rivatives. However, in the case of 6a and 6c, oxidation
took place on the side chains and stopped at the aldehyde
functionality, leaving the aromatic ring untouched. When
the electrolyte was changed to lithium perchlorate (con-
stant current), the reaction was less selective, and the
complex product mixtures were obtained in most cases.
Several products (10-18), of which two are coupling
products (10 and 11), could be isolated and characterized.
Under controlled-potential electrolysis also using lithium
perchlorate and methanol as the electrolyte system but
with aGC as the working electrode, different reactions
took place. A coupling product 19 was isolated, presum-
ably indicating that a coupling reaction first takes place
after the initially formed cation radical among the
different quinone derivatives and side-chain oxidation
and substitution products.
In a typical experiment under base conditions, the same
setup and experimental conditions described above were used,
involving 2 mmol of substrate dissolved or suspended in 30
mL of a 2% KOH-methanol solution. After electrolysis, the
solvent was evaporated under reduced pressure. The oily
residue was neutralized by saturated sodium bicarbonate and
extracted with CHCl3 (3 × 30 mL). The combined organic layer
was evaporated under reduced pressure to remove all of the
solvent and then redissolved in acetone. To a solution of the
corresponding quinone bisketal was added 1-3 drops of
sulfuric acid (0.2 N), and the resulting solution was allowed
to stand for 24 h and consequently dried over MgSO4. After
the evaporation of the solvent, the crude product was purified
by column chromatography on silica gel, eluting with a mixture
of petroleum ether and ethyl acetate with a general increase
of ethyl acetate to give the products.
Exp er im en ta l Section
Cyclic voltammograms were measured by a 273A poten-
tiostat/galvanostat equipped with electrochemical-analysis
software, using a conventional three-electrode cell. The work-
All of the melting points were measured with a melting point
apparatus and are uncorrected. IR spectra were recorded as
J . Org. Chem, Vol. 69, No. 4, 2004 1057

Zeng and Becker
KBr pellets. 1H and 13C NMR spectra were recorded with a
200 MHz spectrometer (200 MHz for the H frequency and 50
2.07 (d, 3H, J ) 1.8 Hz), 3.82 (s, 3H), 5.93 (s, 1H), 6.56 (q, 1H,
J ) 1.8 Hz). 13C NMR (CDCl3) δ: 15.67, 56.11, 102.54, 107.45,
131.20, 146.80, 182.02, 187.58.
1
MHz for the 13C frequency) or a 500 MHz spectrometer (500
MHz for the 1H frequency and 125 MHz for the 13C frequency).
Chemical shifts are given as δ values (internal standard )
TMS). Solvents were chemically pure and were purified by
standard procedures. Compounds 5a and 5c are commercially
available, and 5b20 and 6a -c21 were synthesized according to
the literature procedures. All of the indicated yields are of the
isolated products.
2-Ac e t o x y m e t h y l-5-h y d r o x y m e t h y l-1,4-b e n zo q u i-
n on e (13). Yield: 13% (from 6a under a controlled-potential
condition, LiClO4/MeOH, and GC as the working electrode)
or 5% (from 6a under a constant current, KOH/MeOH, and
1
platinum as the working electrode). H NMR (CDCl3) δ: 2.17
(s, 3H), 4.45 (s, 2H), 4.99 (s, 2H), 6.66 (s, 1H), 6.79 (s, 1H). 13
C
NMR (CDCl3) δ: 20.67, 59.29, 59.45, 131.15, 131.47, 143.37,
147.21, 170.04, 186.89, 187,31, 193.54. IR (KBr) ν: 3454, 1757,
1645, 1435, 1375, and 1232 cm-1. HRMS m/z: calcd for
2-Ch lor om et h yl-1,4-b en zoq u in on e (7b ). Yield: 28%.
1
Mp: 42-44 °C (lit.22 mp 43-45 °C). H NMR (CDCl3) δ: 4.42
C
10H11O5 (M + 1), 211.0606; found, 211.0574.
(d, 2H, J ) 1.71 Hz), 6.81-6.95 (m, 3H).
2-Meth oxym eth yl-5-h yd r oxym eth yl-1,4-qu in on e (14).
2-Hyd r oxym eth yl-1,4-ben zoqu in on e (7c). Yield: 31%.
1
1
Mp: 76-78 °C (lit.23 mp 76-77 °C). H NMR (CDCl3) δ: 4.51
Yield: 6%. Yellow oil. H NMR (CDCl3) δ: 3.46 (s, 3H), 4.31
(d, 2H, J ) 1.9 Hz), 4.55 and 4.56 (d, 1H, J ) 1.9 Hz), 6.76
and 6.77 (t, 1H, J ) 1.9 Hz). IR (KBr) ν: 3450 (br), 2930, 1750
(overtone), 1652, 1457, and 1225 cm-1. HRMS m/z: calcd for
C9H10O4, 182.0629; found, 182.0629. Elem anal. Calcd: C,
59.34; H, 5.49. Found: C, 59.34; H, 5.26.
(d, 2H, J ) 1.88 Hz), 6.77-6.85 (m, 3H).
2,5-Bis(ch lor om eth yl)-1,4-ben zoqu in on e (8). Yield: 32%
(from 6b under a constant current, KOH/MeOH, and platinum
as the working electrode), 7% (from 6b under a controlled-
potential condition, LiClO4/MeOH, and GC as the working
electrode), or 14% (from 6b under a constant current, LiClO4/
MeOH, and platinum as the working electrode). Mp: 100-
2,5-Bis(a cet oxym et h yl)-4,4-d im et h oxycycloh exa -2,5-
1
d ien on e (15). Yield: 39%. H NMR (CDCl3) δ: 2.14 (s, 3H),
1
102 °C (lit.21 mp 97-99 °C). H NMR (CDCl3) δ: 4.43 (d, 4H,
2.17 (s, 3H), 3.29 (s, 6H), 4.89 (d, 1H, J ) 2 Hz), 4.91 (d, 1H,
J ) 1.6 Hz), 6.33 (t, 1H, J ) 2 Hz), 6.75 (1H, J ) 1.6 Hz).
2,5-Dih ydr oxym eth yl-3-m eth oxy-1,4-ben zoqu in on e (16).
J ) 2.2 Hz), 6.97 (t, 2H, J ) 2.2 Hz).
2,5-Dim eth oxyter ep h th a la ld eh yd e (9). Yield: 17 (from
6a under a constant current, KOH/MeOH, and platinum as
the working electrode), 30 (from 6c under a constant current,
KOH/MeOH, and platinum as the working electrode), or 13%
(from 6c under a controlled-potential condition, LiClO4/MeOH,
and GC as the working electrode). Mp: 204-206 °C (lit.9a mp
206-207 °C). 1H NMR (CDCl3) δ: 3.95 (s, 6H), 7.47 (s, 2H),
1
Yield: 7%. Yellow oil. H NMR (CDCl3) δ: 3.39 (s, 3H), 4.47
(d, 2H), 4.73 (s, 2H), 6.81 (t, 1H). IR (KBr) ν: 3512 (br), 2927,
1667, 1150, and 1045 cm-1. HRMS m/z: calcd for C9H10O5,
198.0528; found, 198.0501. Elem anal. Calcd: C, 54.54; H, 5.05.
Found: C, 54.74; H, 5.34.
Deh yd r ocyclic Dim er 17. Yield: 10%. Yellow oil. 1H NMR
(CDCl3) δ: 3.38 (s, 3H), 4.44 (d, J ) 2.4 Hz, 2H), 4.71 (s, 2H),
6.76 (t, 1H, J ) 2.0 Hz), 6.79 (t, 1H, J ) 2.4 Hz). 13C NMR
(CDCl3) δ: 55.52, 59.22, 62.61, 96.41, 131.05, 131.29, 145.70,
147.10, 186.91, 187.67. IR (KBr) ν: 3460 (br), 2942, 1735
(overtone), 1660, 1442, and 1045 cm-1. HRMS m/z: calcd for
10.51 (s, 2H). IR (KBr) ν: 2867, 1682, 1480, and 1397 cm-1
.
2-(2,5-Dim eth oxyben zen e)-4,4-d im eth oxy-5-m eth oxy-
cycloh exa -2,5-d ien on e (10a ). Its X-ray structure has been
determined. Yield: 17%. Mp: 107-108 °C. 1H NMR (CDCl3)
δ: 3.42 (s, 6H), 3.71, 3.75, 3.81 (s, 3H, for each OCH3), 5.47 (s,
1H), 6.31 (s, 1H), 6.75-6.92 (m, 3H). 13C NMR (CDCl3) δ:
51.56, 55.78, 56.37, 56.57, 94.84, 104.87, 112.53, 114.34,
116.76, 125.06, 138.66, 139.58, 151.43, 153.27, 168.22, 184.84.
C
15H10O6, 286.0477; found, 286.0441. Elem anal. Calcd: C,
62.94; H, 3.52. Found: C, 62.39; H, 3.66.
2,5-Bis(a cetoxym eth yl)-1,4-ben zoqu in on e (18). Yield:
38%. Mp: 132-134 °C (lit.21 mp 132-134.5 °C). 1H NMR
(CDCl3) δ: 2.16 (s, 6H), 4.99 (s, 4H), 6.68 (s, 2H).
IR (KBr) ν: 3010, 2935, 1667, 1637, 1630, and 1502 cm-1
HRMS m/z: calcd for C17H20O6, 320.1260; found, 320.1270.
.
2-(2′,5′-Dim eth oxy)-5-m eth oxy-1,4-ben zoqu in on e (19).
Its X-ray structure has been determined. Yield: 18%. Mp:
163-164 °C. 1H NMR (CDCl3) δ: 3.74 (s, 3H), 3.78 (s, 3H),
3.87 (s, 3H), 6.04 (s, 1H), 6.74-6.98 (m, 4H, 1H-Ar and 3H-
quinone). 13C NMR (CDCl3) δ: 55.85, 56.27, 56,38, 108.04,
112.58, 116.04, 116.35, 123.27, 132.64, 146.21, 151.50, 153.43,
158.45, 182.31, 185.75. IR (KBr) ν: 1675 (CdO), 1652, 1600,
and 1487 cm-1. HRMS m/z: calcd for C15H14O5, 274.0841;
found, 274.0810.
2-Met h oxym et h yl-5-m et h oxy-1,4-b en zoqu in on e (20).
Yield: 14 (from 6a ) or 18% (from 6c under a controlled-
potential condition, LiClO4/MeOH, and GC as the working
electrode). Mp: 123-124 °C. 1H NMR (CDCl3) δ: 3,46 (s, 3H),
3.82 (s, 3H), 4.32 (d, 2H, J ) 2.18 Hz), 5.90 (s, 1H), 6.734 (t,
1H, J ) 2.18 Hz). 13C NMR (CDCl3) δ: 56.25, 59.33, 68.00,
107.59, 129.38, 146.54, 158.95, 182.07, 187.19. IR (KBr) ν:
3280, 2890, 1675, and 1480 cm-1. HRMS m/z: calcd for
C9H11O4 (M + 1), 183.0657; found, 183.0640.
2,2-Dim eth oxy-4-(2′,5′-d im eth oxyben zen e)-5-m eth oxy-
cycloh exa -3,5-d ien on e (10b). Its X-ray structure has been
determined. Yield: 17%. Mp: 122-123 °C. 1H NMR (CDCl3)
δ: 3.40 (s, 6H), 3.71, 3.79, 3.86 (s, 3H, for each OCH3), 5.76 (s,
1H), 6.58 (s, 1H), 6.73 (t, 1H, J ) 1.7 Hz), 6.87 (s, 2H, J ) 1.7
Hz). 13C NMR (CDCl3) δ: 50.34, 55.79, 56.31, 56.40, 91.66,
98.69, 102.96, 111.91, 114.20, 116.44, 125.80, 135.11, 135.56,
151.61, 153.35, 169.13, 193.49. IR (KBr) ν: 2995, 2837, 1652,
1585, 1502, and 1375 cm-1. HRMS m/z: calcd for C17H20O6,
320.1260; found, 320.1246.
2,5-Dim eth oxy-4-(2′,5′-d im eth oxyben zyl)p h en ol (11).
Yield: 19%. Mp: 124-126 °C. 1H NMR (CDCl3) δ: 3.72 (s,
3H), 3.74 (s, 3H), 3.79 (s, 3H), 3.85 (s, 3H), 5.67 (s, 1H, Ar-
OH, disappears after the D2O exchanger), 6.67 (s, 1H), 6.80
(s, 1H), 685-6.93 (m, 3H). 13C NMR (CDCl3) δ: 56.34, 56.51,
56,45, 55.68, 99.82, 112.40, 112.88, 114.14, 117.59, 118.26,
128.58, 140.05, 145.67, 151.41, 151.50, 153.27. IR (KBr) ν:
3430, 1525, and 1487 cm-1. HRMS m/z: calcd for C16H18O5,
290.1154; found, 290.1104. Elem anal. Calcd: C, 66.20; H, 6.25.
Found: C, 66.31; H, 6.40.
2,5-Dih yd r oxyt er ep h t h a la ld eh yd e (21). Yield: 22%.
1
Mp: 257-260 °C (lit.25 mp 258-260 °C). H NMR (CDCl3) δ:
7.24 (d, 2H, J ) 0.5 Hz), 9.95 (d, 2H, J ) 0.5 Hz), 10.23 (s,
2-Meth oxy-5-m eth yl-1,4-ben zoqu in on e (12). Yield: 5%.
2H). IR (KBr) ν: 3287, 2927, 1667, and 1472 cm-1
.
1
Mp: 172-173 °C (lit.24 mp 170-171 °C). H NMR (CDCl3) δ:
1,4-Dim eth oxy-2-h ydr oxym eth yl-5-m eth oxym eth ylben -
1
zen e (22). Yield: 18%. Mp: 224-226 °C. H NMR (CDCl3) δ:
(20) Mandell, L.; Cooper, S. M.; Rubin, B.; Campana, C. F.; Day,
R. A., J r. J . Org. Chem. 1983, 48, 3133.
(21) Witiak, D. T.; Loper, J . T.; Ananthan, S.; Almerico, A. M.;
Verhoef, V. L.; Filppi, J . A. J . Med. Chem. 1989, 32, 1636.
(22) O’Shea, K. E.; Fox, M. A. J . Am. Chem. Soc. 1991, 113, 611.
(23) Tamura, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Kita, Y.
Synthesis 1989, 126.
3,53 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 4.50 (d, 2H, J ) 1.08
Hz), 4.82 [m, 2H (H + OH)], 6.52 (s, 1H), 6.59 (s, 1H). IR (KBr)
ν: 3445, 2837, 1720 (overtone), 1615, 1585, 1480, and 1435
cm-1. HRMS m/z: calcd for C11H16O4, 212.1245; found, 212.1255.
(24) Takizawa, Y.; Iwasa, Y.; Suzuki, T.; Miyaji, H. Chem. Lett. 1993,
1863.
(25) Marx, J . N.; Song, P.-s.; Chui, P. K. J . Heterocycl. Chem. 1975,
12, 417.
1058 J . Org. Chem., Vol. 69, No. 4, 2004

Mono- and Disubstituted 1,4-Dimethoxybenzenes
(10a , 10b, and 19) are enclosed. Also included are copies of
Ack n ow led gm en t. The authors are thankful to the
Council for Higher Education (Israel) for granting a
postdoctoral fellowship to C.-C.Z.
1
the H and 13C NMR spectra of the products 10a , 10b, 12, 13,
19, 20, and 22. This material is available free of charge via
the Internet at http://pubs.acs.org.
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawings
and related tables of crystallographic data of three products
J O0302253
J . Org. Chem, Vol. 69, No. 4, 2004 1059