Regioselective reductive demethoxylation of 3,4,5-trimethoxystilbenes

Article abstract of DOI:10.1016/j.tet.2003.08.009

Selective removal of the 4-methoxy group of 3,4,5-trimethoxystilbenes was performed under electron transfer conditions from Na metal in THF. Careful control of reaction conditions and quenching procedure allowed the synthesis of either (E)-3,5-dimethoxystilbenes or 3,5-dimethoxybibenzyls.

Full text of DOI:10.1016/j.tet.2003.08.009

Tetrahedron 59 (2003) 7961–7966
Regioselective reductive demethoxylation of
3,4,5-trimethoxystilbenes
*
Ugo Azzena, Giovanna Dettori, Maria Vittoria Idini, Luisa Pisano and Grazia Sechi
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I 07100 Sassari, Italy
Received 4 June 2003; revised 10 July 2003; accepted 7 August 2003
Abstract—Selective removal of the 4-methoxy group of 3,4,5-trimethoxystilbenes was performed under electron transfer conditions from
Na metal in THF. Careful control of reaction conditions and quenching procedure allowed the synthesis of either (E)-3,5-dimethoxystilbenes
or 3,5-dimethoxybibenzyls.
q 2003 Elsevier Ltd. All rights reserved.
3,5-Dihydroxy-substituted stilbenes, as well as the corre-
sponding bibenzyl derivatives, are an important class of
natural products, which were isolated from many plants1–3
and possess a variety of interesting biological and
pharmacological properties.1–8 Furthermore, it was recently
shown that some 3,5-dimethoxy-substituted-stilbenes are
potent and selective inhibitors of human cytochrome P450
1B1.7 Accordingly, there is a continuous search for new
approaches to their synthesis,3,6–11 most of which rely on
relatively expensive starting materials, as 3,5-dihydroxy-
benzaldehyde or derivatives of 3,5-dihydroxybenzyl
alcohol.
of starting materials; (ii) high regioselectivity; (iii) mild
reaction conditions (Scheme 1).
Scheme 1. Regioselective reductive demethoxylation of 1,2,3-trimethoxy-
benzenes. M¼Na or K; R¼H, n-alkyl, CH(OCH3)2.
Interestingly, 5-substitued derivatives of 1,2,3-trimethoxy-
benzene are particularly cheap and, therefore, attractive
starting materials for similar syntheses, provided the
possibility to operate a regioselective demethoxylation at
the 2-position.
As an extension of this procedure, we wish now to
report that reduction of (E)-3,4,5-trimethoxystilbenes, 1,
with Na metal in dry THF, allows the regioselective removal
of the methoxy group in the 4-position; depending upon
reaction conditions, competitive reduction of the carbon–
carbon double bond occurs,21 leading to the synthesis of
either (E)-3,5-dimethoxystilbenes, 2, or 3,5-dimethoxy-
bibenzyls, 3.22
Despite their generally known inertness and high reductive
potential, the C–O bond of aryl alkyl ethers can be cleaved
by electron transfer from alkali metals in aprotic solvents. In
the course of our extensive studies on the mechanism12–14
and synthetic usefulness12,15–17 of this reaction, we reported
that several derivatives of 1,2,3-trimethoxybenzene undergo
a highly regioselective demethoxylation at the 2-position, in
almost quantitative yield.
1. Results and discussion
3,4,5-Trimethoxybenzaldehyde, a particularly cheap start-
ing material, was reacted with LiAlH4 to afford the
corresponding benzyl alcohol. The crude carbinol was
successively reacted with PBr3 and triethylphosphite,
affording 3,4,5-trimethoxybenzylphosphonate, in 63%
overall yield. According to a general procedure,23 the
phosphonate was deprotonated with NaH in THF, and
reacted with the appropriate arylaldehyde in the presence of
15-crown-5; the corresponding (E)-3,4,5-trimethoxy-
stilbenes, 1a–e, were recovered in good isolated yields
(Scheme 2).
According to this procedure, we reported alternative
syntheses of several naturally occurring 5-substituted and
2,5-disubstituted resorcinols.18–20 The main features of this
approach are the following: (i) cheap and easy availability
Keywords: reduction; electron transfer; regioselectivity; stilbenes.
*
Corresponding author. Tel.: þ39-7922-9549; fax: þ39-7922-9559;
e-mail: ugo@uniss.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.009

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U. Azzena et al. / Tetrahedron 59 (2003) 7961–7966
Scheme 2. Synthesis of (E)-3,4,5-trimethoxystilbenes: i, NaBH4; ii, PBr3; iii, P(OC2H5)3; iv, NaH, 15-crown-5, ArCHO; 1a, Ar¼C6H5, 93%; 1b, Ar¼2-
(CH3O)C6H4, 76%; 1c, Ar¼3-(CH3O)C6H4, 82%, 1d, Ar¼4-(CH3O)C6H4, 76%; 1e, Ar¼3,4,5-(CH3O)3C6H2, 61%.
benzaldehyde, under conventional Wittig olefination
conditions (Scheme 3).
Reductions of stilbenes 1a–e with Na metal were run in dry
THF under Ar; selected results are reported in the Tables 1
and 2 (Scheme 4); it is worth noting that we did not
investigate the formation of phenolic by-products, which
can be obtained by competitive reductive cleavage of
aliphatic carbon–oxygen bonds. Indeed, dealkylation is
usually a minor reaction pathway in the reductive cleavage
of 1,2,3-trimethoxy-substituted benzenes.12
Scheme 3. Synthesis of (E)- and (Z)-3,4,5-trimethoxystilbene, (E)/(Z)-1a,
as a 1:1 mixture of diastereoisomers: i, n-BuLi, THF, 08C, 1 h; ii, 2788C,
ArCHO, 4 h, then 12 h at rt; 69% yield.
Reduction of (E)-3,4,5-trimethoxystilbene, 1a, taken as a
Alternatively, we obtained a 1:1 geometric mixture of (E)-
and (Z)-3,4,5-trimethoxystilbene, 1a, by reacting benzyl-
triphenylphosphonium bromide with 3,4,5-trimethoxy-
model compound, was investigated in some detail (Table 1).
Reaction of 1a with 3 equiv. of Na metal at 08C over 3 h,
followed by aqueous work-up, led to the expected
Table 1. Reductive cleavage of 3,4,5-trimethoxystilbene 1a
Entry
Starting material
Na (equiv.)
T (8C)
t (h)
Quencher
H2O
H2O
H2O
D2O
Br(CH2)2Br
H2O
Br(CH2)2Br
H2O
Products ratioa
2a/3a, 87:13
2a/3a, 72:28
2a/3a, ,5:.95
2a/3a, ,5:.95
2a/3a, .95:,5
2a/3a, ,5:.95
2a/3a, .95:,5
(E)/(Z)-1ad/3a, 45:55
Isolated product, yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
3
6
6
6
6
6
6
1
0
0
3
3
7
7
7
7
7
4
–
–
3a, 78
20
20
20
20
20
20
3a-d2, .95b
2a, 75
1a
(E)/(Z)-1ac
(E)/(Z)-1ac
(E)/(Z)-1ac
–
2a, 73
–
a
1
As determined by H NMR spectroscopy.
b
c
d
1
Deuteration percentage, as determined by H NMR spectroscopy. No incorporation of deuterium on the aromatic ring was detected.
1:1 Mixture of geometric isomers.
4:1 Mixture of geometric isomers.
Table 2. Reductive cleavage of 3,4,5-trimethoxystibenes 1b–e
Entry
Starting material
Na (equiv.)
T (8C)
t (h)
Quencher
H2O
H2O
H2O
D2O
H2O
D2O
Br(CH2)2Br
H2O
H2O
Products ratioa
Isolated product, yield (%)
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1c
1c
1c
1d
1d
1d
1e
1e
6
6
12
12
6
0
0
0
2.5
7
14
14
9
9
7
2
14
6
2b/3b, .95:,5
2b/3b, 52:48
2b/3b, ,5:.95
2b/3b, ,5:.95
2c/3c, ,5:.95
2c/3c, ,5:.95
2c/3c, .95:,5
2d/3d, .95:,5
2d/3d, 69:31
2d/3d, ,5:.95
n.d.e
2b, 75
–
3b, 56
3b-d2, 77b
3c, 89
3c-d2, 86b
2c, 71
2d, 68
–
3a, 65
3e, 69
3e-d2, 25
0
20
20
20
0
6
3
6
6
9
0
10
11
12
6c
20d
20d
20
20
20
H2O
H2O
D2O
18
18
n.d.e
a
1
As determined by H NMR spectroscopy.
b
c
d
e
1
Deuteration percentage, as determined by H NMR spectroscopy. No incorportion of deuterium on the aromatic ring was detected.
In the presence of 1 equiv. of naphthalene.
In the presence of 2 equiv. of naphthalene.
Not determined.

U. Azzena et al. / Tetrahedron 59 (2003) 7961–7966
7963
Scheme 4. Reductive demethoxylation of 3,4,5-trimethoxystilbenes, 1; quench: H2O, D2O, or Br(CH2)2Br; 2a–3a, Ar¼C6H5; 2b–3b, Ar¼2-(CH3O)C6H4;
2c–3c, Ar¼3-(CH3O)C6H4; 2d–3d, Ar¼4-(CH3O)C6H4; 3e, Ar¼3,5-(CH3O)2C6H3.
regioselective demethoxylation at the 4-position affording,
besides bibenzyl 3a (hydropinosilvin dimethyl ether),
(E)-stilbene 2a (pinosilvin dimethyl ether), as major
reaction product (Table 1, entry 1); no trace of the
corresponding (Z)-stereoisomer was detected by H NMR
analysis of the crude reaction mixture.24
methoxy group in the 4-position, thus allowing isolation of
20,3,5-trimethoxystilbene, 2b, in 75% yield (Table 2, entry
1). Increasing the reaction time and the relative amount of
the metal, resulted in competitive reduction of the ethylenic
double bond; reduction with 12 equiv. of Na over 14 h,
followed by quenching with H2O, allowed isolation of
20,3,5-trimethoxybibenzyl 3b (batatasin IV dimethyl ether),
in 56% yield (Table 2, entry 3). Under these conditions,
quenching with D2O led to 77% incorporation of deuterium
at the methylenic positions (Table 2, entry 4).
1
Increasing the relative amount of the metal, as well as
reaction time and temperature, increases the relative amount
of recovered bibenzyl 3a, which was the only reaction
product recovered after running the reduction with 6 equiv.
of Na metal at rt over 7 h (Table 1, entry 3). Under these
conditions, intermediate formation of a dianion was
evidenced by quenching the reaction mixture with D2O:
1H NMR spectroscopy of the crude product showed
quantitative incorporation of deuterium at both benzylic
carbons (Table 1, entry 4). Oxidative quenching of the
reaction mixture with 1.4 equiv. of Br(CH2)2Br led to the
exclusive recovery of stilbene 2a, with no trace of
the corresponding bibenzyl 3a (Table 1, entry 5). It is
worth noting that oxidation of the dianion is highly
stereoselective leading, exclusively, to the formation of
the (E)-stereoisomer.
Similar results were obtained in the reduction of (E)-
3,30,4,5-tetramethoxystilbene, 1c: satisfactory isolated
yields of the corresponding (E)-3,30,5-trimethoxystilbene,
2c (thunalbene dimethylether), and 3,30,5-trimethoxy-
bibenzyl, 3c (batatasin III dimethyl ether), were obtained,
depending upon reaction conditions and quenching
procedure (Table 2, entries 5–7).
Somewhat different re0sults were obtained in the reductive
cleavage of (E)-3,4,4 ,5-tetramethoxystilbene, 1d, which
proved particularly resistant to reduction of the ethylenic
double bond. Indeed, reduction with 6 equiv. of Na metal at
08C over 2 h, allowed the selective removal of the methoxy
group at the 4-position, leading to the recovery of 3,40,5-
trimethoxystilbene, 2d (resverarol trimethyl ether), in 68%
isolated yield (Table 2, entry 8); the main product of this
reaction did not change on increasing the reaction time to
14 h (Table 2, entry 9). We obtained quantitative reduction
of the ethylenic double bond running the reaction at rt, in the
presence of 6 equiv. of the metal and 1 equiv. of
naphthalene. Under these reaction conditions, however, a
double demethoxylation took place, leading to 3,5-
dimethoxybibenzyl, 3a, in 65% isolated yield (Table 2,
entry 10).
To investigate the influence of the geometry at the ethylenic
double bond on this reaction, we reacted Na with a 1:1
mixture of (E) and (Z)-3,4,5-trimethoxystilbene, 1a. With
6 equiv. of Na at rt over 7 h, we obtained bibenzyl 3a, as the
only detected product (Table 1, entry 6). Intermediate
formation of a dianion was evidenced by quenching the
reduction mixture with Br(CH2)2Br; under these conditions,
we recovered (E)-stilbene 2a, as a single geometric isomer,
in 73% isolated yield (Table 1, entry 7). Furthermore, a
reaction performed with 1 equiv. of the metal over 4 h,
allowed the recovery of a mixture containing 3,4,5-
trimethoxystilbene (E)/(Z)-1a, in a 4:1 geometric ratio,
together with (E)-3,5-dimethoxystilbene 2a (55%) (Table 1,
entry 8). It is worth noting that, under these conditions,
reduction of the carbon–carbon double bond did not occur,
and that we did not observe formation of (Z)-3,5-
dimethoxystilbene.
Finally, we investigated the reductive cleavage of hexa-
methoxystilbene 1e. Reductive cleavage of this compound
poses several problems owing to its low solubility in THF
and inertness to electron transfer reduction, probably due to
the presence of six electron donor substituents of the
aromatic rings. After several attempts, we were able to
obtain demethoxylation of the methoxy groups at the 4- and
40-positions, together with reduction of the carbon–carbon
double bond, using 20 equiv. of Na metal in the presence of
2 equiv. of naphthalene. Accordingly, 3,30,5,50-
tetramethoxybibenzyl, 3e, was recovered in 69% isolated
yield (Table 2, entry 11). Under similar reaction conditions,
D2O quenching evidenced only a minor amount of
deuterium incorporation at the benzylic positions (Table 2,
entry 12).
According to the procedure described above, we investi-
gated the reduction with Na metal in THF of stilbenes 1b–e,
bearing methoxyl substituents on both aromatic rings
(Table 2).
Reduction of (E)-20,3,4,5-tetramethoxystilbene, 1b, at rt led
to the formation of several, unidentified, by-products.
Fortunately, reaction of tetramethoxystilbene 1b with
6 equiv. of Na, at 08C, led to selective removal of the

7964
U. Azzena et al. / Tetrahedron 59 (2003) 7961–7966
As a conclusion, we have shown that the methoxy group in
the 4-position of 3,4,5-trimethoxystilbenes can be regio-
selectively removed under reductive electron transfer
conditions. Furthermore, we observed that both reductive
demethoxylation, and isomerization of (Z)- to (E)-stereo-
isomer, are faster than reduction of the ethylenic double bond.
absorption (IR (neat) 3250 cm21), and was not further
characterized.
3,4,5-Trimethoxybenzyl alcohol (10.0 g, 50 mmol),
obtained as described above, was dissolved in 150 mL of
dry CH2Cl2 in a 250 mL two-necked flask equipped with
reflux condenser and magnetic stirrer, under dry N2. The
mixture was chilled to 258C, and a solution of PBr3
(3.5 mL, 10.1 g, 37 mmol), dissolved in CH2Cl2 (10 mL),
was added dropwise. The resulting mixture was stirred for
45 min at 258C. The reaction mixture was poured onto
200 g of ice, neutralized with NaHCO3, and the organic
phase separated. The aqueous phase was extracted with
CH2Cl2 (3£20 mL), and the organic phases were collected,
washed with brine (30 mL), dried (Na2SO4) and evaporated.
The crude product (12.7 g, 49 mmol, 98%) was not further
purified.
However, reduction of the ethylenic double bond of 40-
methoxy-substituted-3,4,5-trimethoxystilbenes 1d and 1e
occurs with concomitant cleavage of the methoxy groups at
the 40-position.
Accordingly, we were able to perform the synthesis of
several resorcinolic (E)-stilbenes, 2, or bibenzyls, 3, from a
common, easily accessible, cheap starting material, by
careful control of reaction conditions (equiv. of the metal,
reaction time and temperature, quenching procedure).
Light yellow oil; dH 3.83 (3H, s, CH3O), 3.86 (6H, s,
2£CH3O), 4.45 (2H, s, CH2), 6.60 (2H, s, 2£ArH) (1H NMR
in agreement with a literature report25); dC 34.2, 56.0, 60.8,
105.9, 133.1, 145.0, 153.2.
2. Experimental
2.1. General
2.2.2. Diethyl 3,4,5-trimethoxybenzylphosphonate. 3,4,5-
Trimethoxybenzylbromide (11.7 g, 45 mmol), obtained as
described above, and triethylphosphite (7.8 mL, 7.46 g,
45 mmol) were mixed in a 100 mL flask equipped with
magnetic stirrer and a fractionating Vigreux column
equipped with a condenser, under dry N2. The flask was
heated at 1408C for 2 h, then at 1808C for 10 min to distil
away all formed ethyl bromide. The reaction mixture was
chilled to rt, diluted with Et2O (30 mL) and H2O (30 mL),
and the organic phase was separated. The aqueous phase
was extracted with Et2O (2£30 mL), the organic phases
were collected, washed with 5% NaOH (30 mL), dried
(Na2SO4) and evaporated. The residue was purified by
fractional distillation, affording 10.4 g (33 mmol, 73%) of a
colourless oil, which was characterized as following.
Boiling and melting points are uncorrected; the air bath
temperature on bulb-to-bulb distillation are given as boiling
points. Starting materials were of the highest commercial
quality and were purified by distillation or recrystallization
immediately prior to use. D2O was 99.8% isotopic purity.
THF was distilled from Na/K alloy under N2 immediately
prior to use. 1H NMR spectra were recorded at 300 MHz and
13C NMR spectra were recorded at 75 MHz in CDCl3 with
SiMe4 as internal standard. Deuterium incorporation was
1
calculated by monitoring the H NMR spectra of crude
reaction mixtures, and comparing the integration of the
signal corresponding to protons in the arylmethyl position
with that of known signals. Resonances of the CHD protons
are usually shifted 0.02–0.04 ppm (d) upfield relative to the
resonances of the corresponding CH2 protons. Flash
chromatography was performed on Merck silica gel 60
(40–63 mm), and TLC analyses on Macherey–Nagel silica
gel pre-coated plastic sheets (0.20 mm). Elemental analyses
were performed by the microanalytical laboratory of the
Bp 1708C/1 mm Hg; dH 1.27 (6H, t, J¼7.2 Hz, 2£CH3), 3.09
(2H, d, J¼21.3 Hz, CH2P), 3.83 (3H, s, CH3O), 3.85 (6H, s,
2£CH3O), 3.98–4.09 (4H, m, 2£CH2O), 6.53 (2H, d,
J¼2.7 Hz, 2£ArH) (1H NMR in agreement with a literature
report26); dC 16.3 (d, J¼6 Hz), 33.8 (d, J¼138 Hz), 56.0, 60.7,
62.0(d, J¼7 Hz), 106.7 (d, J¼7 Hz), 126.9 (d, J¼9 Hz), 136.8
`
Dipartimento di Chimica, Universita di Sassari.
2.2. Preparation of starting materials
(d, J¼4 Hz), 153.0 (d, J¼3 Hz); IR (neat) 1580 cm21
.
2.2.1. 3,4,5-Trimethoxybenzylbromide. 3,4,5-Trimethoxy-
benzaldehyde (15.0 g, 76 mmol) was dissolved in 150 mL
of CH3OH in a 250 mL two-necked flask equipped with
reflux condenser and magnetic stirrer, under dry N2. The
solution was chilled to 08C and NaBH4 (3.5 g, 92 mmol,
1.2 equiv.) was added in small portions over 1 h. The
resulting mixture was stirred overnight at rt. The solvent
was evaporated, and the residue partitioned between Et2O
(30 mL) and H2O (30 mL), stirred for a few min, and the
organic phase separated. The aqueous phase was extracted
with Et2O (2£30 mL), the organic phases were collected,
washed with brine (30 mL), dried (Na2SO4) and evaporated.
(E)-3,4,5-Trimethoxystilbenes 1a–e were synthesized
according to a general procedure described in Ref. 23;
isolated yields are reported in Scheme 2. Compounds 1a,27
1c,28 1d28 and 1e29 are already known, and were
characterized by comparison with literature data. Com-
pound 1b28 is already known, but not described. Accord-
ingly, it was characterized as follows.
2.2.3. (E)-20,3,4,5-Tetramethoxystilbene, 1b. Purified by
flash chromatography (petroleum ether/AcOEt¼1:1),
colourless oil, which solidifies upon standing; Rf¼0.36
(petroleum ether/AcOEt¼1:1); mp 79–808C (AcOEt/
petroleum ether); (Found: C, 71.85; H 6.92; C18H20O4
requires C, 71.97; H, 6.73); dH 3.87 (3H, s, CH3O), 3.90
(3H, s, CH3O), 3.92 (6H, s, 2£CH3O), 6.76 (2H, s, 2£ArH),
6.88–7.01 (2H, m, 2£ArH), 7.05 (1H, d, J¼16.2 Hz, CH),
The crude product (13.3 g, 67 mmol, 88%) appeared
homogeneous by TLC analysis Rf¼0.25 (petroleum ether/
AcOEt¼7:3), did not show any IR carbonyl stretching

U. Azzena et al. / Tetrahedron 59 (2003) 7961–7966
7965
7.22–7.31 (1H, m, ArH), 7.37 (1H, d, J¼16.2 Hz, CH), 7.58
(1H, dd, J¼7.5, 1.8 Hz, ArH); dC 55.5, 56.1, 60.9, 103.5,
110.9, 120.7, 122.9, 126.2, 126.4, 128.6, 129.1, 133.7,
Quenching with Br(CH2)2Br (1.4 equiv.) was performed by
slow dropwise addition of the electrophile to the reduction
mixture chilled at 08C, followed by aqueous work up as
described above.
138.1, 153.3, 156.8; IR (neat) 1573 cm21
.
2.2.4. Synthesis of (E)- and (Z)-3,4,5-trimethoxystilbene,
(E)/(Z)-1a. n-Butyllithium (4.8 mL of a 1.6 M solution in
hexane, 7.7 mmol) was added dropwise to a magnetically
stirred solution of benzyltriphenylphosphonium bromide
(3.35 g, 7.7 mmol) in dry THF (10 mL), chilled at 08C under
an Ar atmosphere. After the mixture was stirred for 1 h, the
reaction temperature was lowered to 2788C, and a solution
of 3,4,5-trimethoxybenzaldehyde (1.50 g, 7.6 mmol) dis-
solved in dry THF (5 mL) was added dropwise. Stirring was
continued at 2788C for 4 h, the reaction mixture was
allowed to warm to rt, and stirred for 12 h. The reaction
mixture was diluted with petroleum ether (10 mL) and H2O
(10 mL), and the organic phase was separated. The aqueous
phase was extracted with Et2O (2£20 mL), the organic
phases were collected, washed with 1N HCl (10 mL),
saturated NaHCO3 (10 mL), H2O (10 mL), dried (Na2SO4)
and evaporated. The residue was purified by flash
chromatography (petroleum ether/AcOEt¼9:1, Rf: (E)-
isomer¼0.20, (Z)-isomer¼0.28), to afford a white solid
(1.46 g, 5.7 mmol, 69%), consisting of a 1:1 diastereo-
isomeric mixture of (E)- and (Z)-3,4,5-trimethoxystilbene.
The composition of this mixture was determined comparing
Crude products were purified and characterized as follows.
2.3.1. (E)-3,5-Dimethoxystilbene (2a). Purified by flash
chromatography (petroleum ether/AcOEt¼7:3), colourless
oil, which solidifies upon standing; Rf¼0.50 (petroleum
(lit.,30
ether/AcOEt¼7:3);
bp
1808C/1 mm Hg
1238C/0.02 mm Hg); dH 3.79 (6H, s, 2£CH3O), 6.38
(1H, t, J¼2.1 Hz, ArH), 6.66 (2H, d, J¼2.1 Hz, 2£ArH),
7.01 (1H, d, J¼16.5 Hz, CH), 7.07 (1H, d, J¼16.5 Hz,
CH), 7.21–7.28 (1H, m, ArH), 7.30–7.38 (2H, m, 2£ArH),
7.45–7.51 (2H, m, 2£ArH); dC 55.2, 99.9, 104.5,
126.5, 127.6, 128.6, 129.1, 137.0, 139.3, 160.9; IR (neat)
1580 cm21
.
2.3.2. 3,5-Dimethoxybibenzyl (3a). Purified by flash
chromatography (petroleum ether/AcOEt¼9:1); colourless
oil; Rf¼0.41 (petroleum ether/AcOEt¼9:1); bp 1308C/
1 mm Hg (lit.,31 86–888C/0.1 mm Hg); dH 2.81–2.95 (4H,
m, 2£CH2), 3.76 (6H, s, 2£CH3O), 6.31 (1H, t, J¼2.1 Hz,
ArH), 6.34 (2H, d, J¼2.1 Hz, 2£ArH), 7.15–7.22 (3H, m,
3£ArH), 7.25–7.31 (2H, m, 2£ArH); dC 37.7, 38.2, 55.2,
97.9, 106.5, 125.9, 128.3, 128.4, 141.7, 144.2, 160.7.
1
its H NMR spectrum with literature spectra of authentic
samples.27,28
2.3.3. (E)-20,3,5-Trimethoxystilbene (2b). Purified by flash
chromatography (petroleum ether/AcOEt¼9:1), colourless
oil; Rf¼0.37 (petroleum ether/AcOEt¼9:1); bp 1858C/
1 mm Hg; dH 3.81 (6H, s, 2£CH3O), 3.87 (3H, s, CH3O),
6.38 (1H, t, J¼2.4 Hz, ArH), 6.69 (2H, d, J¼2.4 Hz,
2£ArH), 6.89 (1H, d, J¼7.8 Hz, ArH), 6.96 (1H, t,
J¼7.8 Hz, ArH), 7.04 (1H, d, J¼16.6 Hz, CH), 7.22 (1H,
td, J¼7.8, 1.8 Hz, ArH), 7.46 (1H, d, J¼16.6 Hz, CH), 7.57
(1H, dd, J¼7.8, 1.8 Hz, ArH); dC 55.2, 55.3, 99.6, 104.5,
110.8, 123.9, 126.0, 126.4, 128.7, 128.9, 139.9, 156.8, 160.8
(1H and 13C NMR in agreement with a literature report32);
2.2.5. (Z)-3,4,5-Trimethoxystilbene. Purified by flash
chromatography (petroleum ether/AcOEt¼9:1), colourless
oil; Rf¼0.28 (petroleum ether/AcOEt¼91); dH 3.64 (6H, s,
2£CH3O), 3.83 (3H, s, CH3O), 6.46 (2H, s, 2£ArH), 6.50 (1H,
d, J¼12.4 Hz, CH), 6.60 (1H, d, J¼12.4 Hz, CH), 7.23–7.35
(5H, m) (1H NMR in agreement with a literature report28).
2.3. Reduction of trimethoxystilbenes 1. General
procedure
IR (neat) 1590 cm21
.
Two to three pieces of freshly cut Na metal (3–20 equiv.,
see Tables 1 and 2) were placed under Ar in a 50 mL two-
necked flask equipped with reflux condenser and magnetic
stirrer, and suspended in dry THF (5 mL) at the reported
temperature (Tables 1 and 2). The appropriate stilbene
(3 mmol), dissolved in dry THF (5 mL) was added
dropwise, each metal piece was cut into 2–3 smaller pieces
with a spatula, and the reaction mixture was vigorously
stirred for the reported time (Tables 1 and 2).
2.3.4. 20,3,5-Trimethoxybibenzyl (3b). Purified by flash
chromatography (petroleum ether/AcOEt¼9:1); colourless
oil; Rf¼0.41 (petroleum ether/AcOEt¼9:1); bp 1758C/
1 mm Hg; (Found: C, 74.77; H 7.63; C17H20O3 requires C,
74.96; H, 7.42); dH 2.71–2.95 (4H, m, 2£CH2), 3.74 (6H, s,
2£CH3O), 3.81 (3H, s, CH3O), 6.30 (1H, t, J¼2.4 Hz, ArH),
6.37 (2H, d, J¼2.4 Hz, 2£ArH), 6.83–6.91 (2H, m,
2£ArH), 7.09–7.12 (1H, m, ArH), 7.14–7.22 (1H, m,
ArH); dC 32.2, 36.4, 55.1, 55.2, 97.7, 106.4, 110.1, 120.3,
127.1, 129.8, 130.0, 144.8, 157.4, 160.6.
The reaction mixture was chilled to 08C and quenched by
slow dropwise addition of H2O (10 mL: Caution! Na metal
reacts violently with H2O, with evolution of H2; quenching
must be operated under inert atmosphere), the cold bath
removed and, after several minutes stirring at rt, the
resulting mixture extracted with Et2O (3£10 mL). The
organic phases were collected, washed with brine (10 mL),
dried (Na2SO4) and the solvent distilled off.
2.3.5. (E)-3,30,5-Trimethoxystilbene (2c). Purified by flash
chromatography (petroleum ether/AcOEt¼7:3), colourless
oil; Rf¼0.48 (petroleum ether/AcOEt¼7:3); bp 1908C/
1 mm Hg; dH 3.83 (6H, s, 2£CH3O), 3.85 (3H, s, CH3O),
6.40 (1H, t, J¼2.1 Hz, ArH), 6.67 (2H, d, J¼2.1 Hz,
2£ArH), 6.82 (1H, ddd, J¼8.1, 2.7, 0.6 Hz, ArH), 7.01 (1H,
d, J¼17.4 Hz, CH), 7.07 (1H, d, J¼17.4 Hz, CH), 7.04–
7.12 (2H, m, ArH), 7.27 (1H, t, J¼8.1, ArH); dC 55.2, 55.3,
100.0, 104.6, 111.7, 113.4, 119.3, 128.9, 129.1, 129.6,
138.5, 139.2, 159.8, 160.9 (1H and 13C NMR in agreement
D2O quenching was performed by slow dropwise addition
of 1 mL of the electrophile to the reduction mixture
chilled at 08C, followed by aqueous work-up as described
above.
with a literature report32); IR (neat) 1590 cm21
.

7966
U. Azzena et al. / Tetrahedron 59 (2003) 7961–7966
2.3.6. 3,30,5-Trimethoxybibenzyl (3c). Purified by flash
chromatography (petroleum ether/AcOEt¼9:1); colourless
oil; Rf¼0.37 (petroleum ether/AcOEt¼9:1); bp 1608C/
1 mm Hg; dH 2.75–2.84 (4H, m, 2£CH2), 3.67 (6H, s,
2£CH3O), 3.69 (3H, s, CH3O), 6.23 (1H, t, J¼2.4 Hz, ArH),
6.26 (2H, d, J¼2.4 Hz, 2£ArH), 6.62–6.74 (3H, m,
3£ArH), 7.09–7.16 (1H, m, ArH) (1H NMR in agreement
with a literature report33); dC 37.7, 38.0, 55.1, 55.2, 97.9,
106.4, 111.2, 114.1, 120.8, 129.3, 143.3, 144.1, 159.6, 160.7.
´
11. Alonso, E.; Ramon, D. J.; Yus, M. J. Org. Chem. 1997, 62,
417–421.
12. Azzena, U. Trends Org. Chem. 1997, 6, 55–65, and references
therein.
13. Casado, F.; Pisano, L.; Farriol, M.; Gallardo, I.; Marquet, J.;
Melloni, G. J. Org. Chem. 2000, 65, 322–331.
´
14. Pisano, L.; Farriol, M.; Asensio, X.; Gallardo, I.; Gonzalez-
Lafont, A.; Lluch, J. M.; Marquet, J. J. Am. Chem. Soc. 2002,
124, 4708.
15. Azzena, U.; Melloni, G.; Pisano, L. J. Chem. Soc., Perkin
Trans. 1 1995, 261–266.
2.3.7. (E)-3,40,5-Trimethoxystilbene (2d). Purified by flash
chromatography (petroleum ether/AcOEt¼9:1), colourless
oil, which solidifies upon standing; Rf¼0.54 (petroleum
ether/AcOEt¼9:1); mp 52–548C (CH3OH) (lit.,27 56.5–
57.58C, CH3OH); dH 3.70 (3H, s, CH3O), 3.71 (6H, s,
2£CH3O), 6.28 (1H, t, J¼2.1 Hz, ArH), 6.55 (2H, d,
J¼2.1 Hz, 2£ArH), 6.75–6.80 (2H, m, 2£ArH), 6.79 (1H, d,
J¼16.5 Hz, CH), 6.94 (1H, d, J¼16.5 Hz, CH), 7.30–7.35
(2H, m, 2£ArH); dC 55.2, 55.2, 99.5, 104.2, 114.0, 126.4,
16. Azzena, U.; Melloni, G.; Piroddi, A. M.; Azara, E.; Contini, S.;
Fenude, E. J. Org. Chem. 1992, 57, 3101–3106, and
references therein.
17. Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org.
Chem. 1990, 55, 5386–5390.
18. Azzena, U.; Denurra, T.; Fenude, E.; Melloni, G.; Rassu, G.
Synthesis 1989, 28–30.
19. Azzena, U.; Cossu, S.; Denurra, T.; Melloni, G.; Piroddi, A. M.
Synthesis 1990, 313–314.
127.7, 128.6, 129.8, 139.6, 159.3, 160.9; IR(neat) 1590 cm21
.
20. Azzena, U.; Idini, M. V.; Pilo, L. Synth. Commun. 2003, 33,
1309–1317.
2.3.8. 3,40,5-Trimethoxybibenzyl (3d). Partially purified
by flash chromatography (petroleum ether/AcOEt¼9:1);
colourless oil; Rf¼0.48 (petroleum ether/AcOEt¼9:1); dH
2.76–2.84 (4H, m, 2£CH2), 3.76 (6H, s, 2£CH3O), 3.78
(3H, s, CH3O), 6.24 (1H, t, J¼2.1 Hz, ArH), 6.26 (2H, d,
J¼2.1 Hz, 2£ArH), 6.67–6.74 (2H, m, 2£ArH), 6.94–7.05
(2H, m, 2£ArH) (1H NMR in agreement with a literature
report34); this product was not further characterized.
21. Reduction of stilbene with alkali metals in ethereal solvents,
leading to the formation of dianionic intermediates, was
already investigated: (a) Schlenk, W.; Bergmann, E. Liebigs
Ann. Chem. 1928, 463, 1–322, (particularly pages 106–117),
and references therein. (b) Smith, J. G.; Oliver, E.; Boettger,
T. J. Organometallics 1983, 2, 1577–1582, and references
therein.
22. Methyl ethers of resorcinolic stilbenes and bibenzyls can be
easily hydrolysed to the corresponding hydroxy derivatives;
see, for example, Ref. 6.
2.3.9. 3,30,5,50-Tetramethoxybibenzyl (3e). Purified by
flash chromatography (petroleum ether/AcOEt¼8:2), white
solid; Rf¼0.32 (petroleum ether/AcOEt¼8:2); mp 105–
1068C (AcOEt) (lit.,35 106–1088C, CH2Cl2/petroleum
ether); dH 2.85 (4H, s, 2£CH2), 3.77 (12H, s, 4£CH3O),
6.32 (2H, t, J¼2.1 Hz, 2£ArH), 6.36 (4H, d, J¼2.1 Hz,
4£ArH); dC 38.0, 55.3, 98.0, 106.5, 144.1, 160.8.
23. Baker, R.; Sims, R. J. Synthesis 1981, 117.
24. (E)- and (Z)-3,5-dimethoxystilbene exhibit very different H
1
NMR spectra: Ali, M. A.; Kondo, K.; Tsuda, Y. Chem. Pharm.
Bull. 1992, 40, 1130–1136. see also (b) Suga, T.; Ohta, S.;
Munesada, K.; Ide, N.; Kurokawa, M.; Shimizu, M.; Ohta, E.
Phytochemistry 1993, 33, 1395–1401.
25. Olszewski, J. D.; Marshalla, M.; Sabat, M.; Sundberg, R. J.
J. Org. Chem. 1994, 59, 4285–4296.
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