Synthesis of antibiotic stilbenes by reductive metalation of 3,4,5-trimethoxybenzaldehyde dimethyl acetal

Article abstract of DOI:10.1081/SCC-120018690

Reductive metalation of 3,4,5-trimethoxybenzaldehyde dimethyl acetal followed by reaction with suitable electrophiles is the key step of a reaction sequence leading to the synthesis of naturally occurring 4-alkyl-3,5-dihydroxy-substituted trans-stilbenes

Full text of DOI:10.1081/SCC-120018690

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Synthesis of Antibiotic Stilbenes by Reductive
Metalation of 3,4,5-Trimethoxybenzaldehyde Dimethyl
Acetal
Ugo Azzena a , Maria Vittoria Idini a & Luciano Pilo a
a Dipartimento di Chimica e Facoltà di Farmacia , Università di Sassari , Sassari, Italy
Published online: 15 Aug 2006.
To cite this article: Ugo Azzena , Maria Vittoria Idini & Luciano Pilo (2003) Synthesis of Antibiotic Stilbenes by Reductive
Metalation of 3,4,5-Trimethoxybenzaldehyde Dimethyl Acetal, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:8, 1309-1317, DOI: 10.1081/SCC-120018690
To link to this article: http://dx.doi.org/10.1081/SCC-120018690
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 8, pp. 1309–1317, 2003
Synthesis of Antibiotic Stilbenes by Reductive
Metalation of 3,4,5-Trimethoxybenzaldehyde
Dimethyl Acetal
*
Ugo Azzena, Maria Vittoria Idini, and Luciano Pilo
Dipartimento di Chimica e Facolta di Farmacia,
Universita di Sassari, Sassari, Italy
ABSTRACT
Reductive metalation of 3,4,5-trimethoxybenzaldehyde dimethyl
acetal followed by reaction with suitable electrophiles is the key
step of a reaction sequence leading to the synthesis of naturally
occurring 4-alkyl-3,5-dihydroxy-substituted trans-stilbenes having
antibiotic activity.
Because 30,50-dihydroxy-substituted stilbenes are an important class
of natural products with significant biological and pharmacological
properties,[1–6] there is a continuous search for new approaches to their
*Correspondence: Ugo Azzena, Dipartimento di Chimica e Facolta di Farmacia,
Universita di Sassari, via Vienna 2, 07100 - Sassari, Italy; Fax: þ39-07-922-9559;
E-mail: ugo@ssmain.uniss.it.
1309
DOI: 10.1081/SCC-120018690
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1310
Azzena, Vittoria Idini, and Pilo
synthesis.[1–3,7–9] Even if relatively expensive, dimethyl- or dimethoxy-
methyl ethers of 3,5-dihydroxybenzaldehyde (or derivatives thereof) are
widely employed as starting materials for these syntheses.[1–3,8,9] As an
alternative, organomanganese complexes of 1,3-dimethoxy-2-alkyl-
benzenes were proposed as starting materials.[7]
We already reported a synthetic procedure involving the regio-
selective reductive electrophilic substitution of the 2-methoxy group of
5-substituted derivatives of 1,2,3-trimethoxybenzene under electron-
transfer conditions from alkali metals, leading to the synthesis of several
5-alkyl-substituted- (olivetol and its homologues)[10] and 2,5-dialkyl-
substituted-resorcinols (stemphol and DB2073).[11]
The main features of this approach are the following: (i) cheap
and easily available starting materials; (ii) high regioselectivity; (iii)
intermediate formation of 2,6-dimethoxy-substituted organometals; (iv)
reaction conditions allowing the introduction of several functionalities
which are, in principle, not stable to reduction with alkali metals.[12,13]
We investigated further the usefulness of this approach, and wish
now to report the application of this procedure to the synthesis of two
natural antibiotic metabolites with a 4-alkyl-3,5-dihydroxy-substituted
trans-stilbene structure, namely (E )-1,3-dimethoxy-2-ethyl-5-(2-phenyl-
ethenyl)benzene, 4a, and (E )-1,3-dimethoxy-2-(1-methylethyl)-5-(2-phe-
nylethenyl)benzene, 4b. Conversion of these compounds into the
corresponding natural 3,5-dihydroxystilbenes was achieved according
to an established procedure.[7]
RESULTS AND DISCUSSION
The syntheses of the desired antibiotic stilbenes 5a and 5b were
realized according to the Sch. 1.
The dimethyl acetal of 3,4,5-trimethoxybenzaldehyde, 1, is commer-
cially available or can be easily prepared by reaction of the corresponding
aldehyde with HC(OCH3)3 in CH3OH in the presence of NH4Cl.[11]
Regioselective reductive metalation at the 4-position was accomplished
with Na metal in THF for 24 h at r.t. The corresponding intermediate
organosodium derivative 2 was reacted with EtBr to afford, after acidic
work up, the corresponding 3,5-dimethoxy-4-ethylbenzaldehyde, 3a, in
68% overall yield.
According to a general procedure,[14] Wadsworth–Emmons olefina-
tion of aldehyde 3a with the sodium salt of diethyl benzylphosphonate in
THF in the presence of a catalytic amount of 15-crown-5 afforded,

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Antibiotic Stilbenes by Reductive Metalation
1311
Scheme 1.
stereoselectively, (E )-1,3-dimethoxy-2-ethyl-5-(2-phenylethenyl)benzene,
4a, in 80% isolated yield.
Demethylation to the corresponding biologically active resorcinol 5a
was accomplished with BBr3-Me2S in refluxing 1,2-dichloroethane,
according to a literature procedure.[7]
A relatively different reaction sequence was devised to obtain the
iso-propyl derivative 5b. As a matter of fact, reaction of the organosodium
derivative 2 with secondary alkyl halides does not afford the desired alky-
lated compounds.[11,13] Therefore, the iso-propyl chain in the 4-position
was introduced according to a more complex reaction pathway.
Intermediate 2 was generated as reported above and reacted at À40ꢀC
with an excess of methyl chloroformate for 2 h, followed by addition of
Et3N to avoid hydrolysis of the acetal moiety during aqueous work up.
According to this procedure, methyl 2,6-dimethoxy-4-dimethoxymethyl-
benzoate, 3b, was obtained in 75% isolated yield.

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Azzena, Vittoria Idini, and Pilo
The methyl ester was reacted with excess CH3MgI leading, after acidic
workup, to3,5-dimethoxy-4-methylethenylbenzaldehyde, 3c, in69%yield.
Conversion of unsaturated aldehyde 3c into saturated aldehyde 3d
via selective hydrogenation of the C–C double bond failed under a variety
of reaction conditions, leading to no reaction (hydrogenation in EtOH
over 5% Pd/C(en)[15] or NaBH4 reduced PdCl2[16]), or to contemporary
reduction of the aldehyde moiety (hydrogenation over 10 or 5% Pd/C in
EtOH or in THF).
On the contrary, reaction of aldehyde 3c with trimethyl orthoformate
in the presence of a catalytic amount of NH4Cl afforded the correspond-
ing acetal, which was hydrogenated at atmospheric pressure and r.t. over
5% Pd/C in EtOH; acidic hydrolysis led to 2,6-dimethoxy-4-methylethyl-
benzaldehyde, 3d, in 65% isolated yield.
According to the above reported procedure,[14] Wadsworth–Emmons
olefination of aldehyde 3d afforded stereoselectively the desired stilbene
4b in 78% yield[17]; the last one was converted into the corresponding
resorcinol 5b as described in the literature.[7]
In conclusion, the dimethyl acetal of 3,4,5-trimethoxybenzaldehyde
is a particularly cheap starting material which can be elaborated into
biologically active 4-alkyl-substituted resorcinolic stilbenes through a
reaction sequence involving regioselective reductive metalation as a key
synthetic step.
EXPERIMENTAL
Boiling and melting points are uncorrected; the air bath tempera-
ture on bulb-to-bulb distillations is given as boiling points. Starting
materials were of the highest commercial quality and were purified by
distillation or crystallization. THF was distilled from Na/K alloy under
dry N2 immediately prior to use. 1H NMR spectra were recorded at
300 MHz and 13C NMR at75 MHz in CDCl with SiMe4 as internal
3
standard. IR spectra were recorded in nujol. Elemental analyses were
performed by the Microanalytical Laboratory of the Dipartimento di
Chimica, Universita di Sassari. Resorcinols 5a and 5b were obtained by
demethylation of the corresponding ethers 4a and 4b, respectively,
according to a known procedure,[7] and characterized by comparison
with literature data.
3,5-Dimethoxy-4-ethylbenzaldehyde (3a): Freshly cutNa metal (0.57 g,
25 mg atom) was placed under dry Ar in a two-necked flask equipped
with reflux condenser and magnetic stirrer, and suspended in anhydrous

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Antibiotic Stilbenes by Reductive Metalation
1313
THF (50 mL). The mixture was chilled to 0ꢀC and a solution of 1 (2 g,
8.3 mmol) in anhydrous THF (20 mL) was added dropwise. The reaction
mixture was stirred at r.t. for 24 h, then cooled to 0ꢀC, and a solution
of EtBr (1.8 g, 1.2 mL, 17 mmol) dissolved in THF (5 mL) was added
dropwise. After stirring 12 h at r.t., the reaction mixture was quenched
by careful dropwise addition of H2O (20 mL, CAUTION!). Et2O was
added (20 mL) and the organic phase separated. The aqueous phase
was extracted with Et2O (3 Â 20 mL) and the organic phase washed
with H2O (20 mL) and evaporated. The residue was dissolved in
THF/1N HCl (1:1, 50 mL) and stirred at r.t. for 5 h. The mixture was
extracted with Et2O (3 Â 20 mL), the organic phase washed with H2O
(2 Â 20 mL), dried (Na2SO4), and the solvent evaporated. The residue
was purified by flash chromatography (AcOEt/Et. Petr. ¼ 3:7, Rf ¼ 0.61)
to afford pure 3a (1.1 g, 5.2 mmol, 68%), characterized as follows: white
solid, m.p. 68ꢀC (i-PrOH/H2O) (lit.[11] 68–69ꢀC); H NMR ꢀ 1.08 (3H, t,
1
J ¼ 7.3 Hz, CH3), 2.62 (2H, q, J ¼ 7.3 Hz, CH2), 3.89 (6H, s, OCH3), 7.05
(2H, s, HAr), 9.90 (1H, s, CHO); IR ꢁ ¼ 1680 cmÀ1
.
(E )-1,3-Dimethoxy-2-ethyl-5-(2-phenylethenyl)benzene (4a): NaH
(5.7 mmol, 0.2 g of a 60% dispersion in mineral oil) was placed under
dry Ar in a two-necked flask equipped with reflux condenser and mag-
netic stirrer, washed with anhydrous THF (3 Â 10 mL) and suspended in
anhydrous THF (15 mL) containing 15-crown-5 (30 mg). The mixture was
chilled to 0ꢀC and a solution of diethyl benzylphosphonate (1.19 g,
1.1 mL, 5.2 mmol) and 3a (1.1 g, 5.2 mmol) in THF (10 mL) was added
dropwise. The mixture was stirred at r.t. overnight, then quenched by
slow dropwise addition of H2O (20 mL). Et2O was added (20 mL), the
organic phase separated and the aqueous phase was extracted with Et2O
(2 Â 20 mL). The organic phase was washed with H2O (20 mL), dried
(Na2SO4), and the solvent evaporated. The residue was purified by
flash chromatography (AcOEt/Et. Petr. ¼ 3:7, Rf ¼ 0.49) to afford pure
4a (1.1 g, 4.2 mmol, 80%), characterized as follows: colorless oil, which
solidifies upon standing, m.p. 75–76ꢀC (lit.[7] m.p. 73.5–74.5ꢀC); 1H NMR
ꢀ 1.09 (3H, t, J ¼ 7.5 Hz, CH3), 2.67 (2H, q, J ¼ 7.5 Hz, CH2), 3.86 (6H, s,
OCH3), 6.69 (2H, s, HAr), 7.06 (2H, s, 2 Â CH), 7.24 (1H, t, J ¼ 7.2 Hz,
HAr), 7.34 (2H, t, J ¼ 7.5 Hz, HAr), 7.52 (2H, d, J ¼ 7.2 Hz, HAr);
13C NMR ꢀ 13.8, 16.4, 55.7, 102.2, 120.9, 126.4, 127.5, 127.8, 128.6,
129.2, 135.8, 137.4, 158.2; IR ꢁ ¼ 1590, 1560 cmÀ1
.
Methyl 2,6-dimethoxy-4-dimethoxymethylbenzoate (3b): Freshly cut
Na metal (1.57 g, 68 mg atom) was placed under dry Ar in a two-necked
flask equipped with reflux condenser and magnetic stirrer, and suspended
in anhydrous THF (100 mL). The mixture was chilled to 0ꢀC and
a solution of 1 (5 g, 21 mmol) in anhydrous THF (40 mL) was added

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Azzena, Vittoria Idini, and Pilo
dropwise. The reaction mixture was stirred at r.t. for 24 h, then cooled to
À40ꢀC and a solution of ClCOOCH3 (6.0 g, 4.9 mL, 63 mmol) dissolved in
THF (10 mL) was added dropwise. After stirring 2 h at À40ꢀC,
Et3N (12 mL) was added and the mixture stirred for 10 min before
quenching itwiht H 2O (20 mL, CAUTION!). Et2O was added (50 mL),
the organic phase separated and the aqueous phase extracted with Et2O
(2 Â 30 mL). The organic phase was washed with H2O (50 mL), dried
(Na2SO4), and the solvent evaporated. The residue was purified by
flash chromatography (AcOEt/Et. Petr. ¼ 4:6, Rf ¼ 0.44) to afford pure
3b (4.3 g, 15.8 mmol, 75%), characterized as follows: white solid, m.p.
67–70ꢀC (CH3OH); 1H NMR ꢀ 3.31 (6H, s, 2 Â OCH3) 3.83 (6H, s,
2 Â OCH3) 3.90 (3H, s, OCH3), 5.35 (1H, s, CH), 6.67 (1H, s, HAr);
13C NMR ꢀ 52.4, 52.5, 56.1, 102.4, 102.4, 141.7, 157.3, 166.9; IR
ꢁ ¼ 1745, 1600 cmÀ1. Anal. calc. for C13H18O6: C 57.76; H 6.73. Found:
C 57.49; H 6.91.
3,5-Dimethoxy-4-methylethenylbenzaldehyde (3c): Mg turnings
(1.13 g, 46 mmol) were placed under dry Ar in a two-necked flask
equipped with reflux condenser and magnetic stirrer, and suspended
in a minimal amountof anhydrous Et O. To this mixture, a solution
2
of CH3I (6.5 g, 2.9 mL, 46 mmol) in Et2O (30 mL) was added dropwise,
and stirring was continued overnight at r.t. Then, 3b (3.8 g, 14 mmol)
dissolved in Et2O (30 mL), containing a minimal amount of THF to
complete solubilization, was added dropwise, and the mixture refluxed
for 12 h. The mixture was hydrolyzed by slow dropwise addition of
H2SO4 2 N (20 mL), the organic phase separated and the
aqueous phase extracted with Et2O (3 Â 20 mL). The organic phase was
evaporated and the residue dissolved in THF/H2SO4 4N ¼ 1:1 (20 mL)
and refluxed for 8 h. The mixture was chilled to r.t., extracted with Et2O
(3 Â 20 mL), the organic phase washed with H2O (20 mL), sat. NaHCO3
(20 mL), dried (Na2SO4) and the solvent evaporated. The residue
was purified by crystallization (CH3OH) to afford pure 3c (2.0 g,
9.7 mmol, 69%), characterized as follows: white solid, m.p. 98ꢀC
(CH3OH) (lit.[18] m.p. 97–98ꢀC); 1H NMR ꢀ 2.02 (3H, dd, J ¼ 1.5,
1.2 Hz, CH3), 3.89 (6H s, OCH3), 4.89 (1H, qd, J ¼ 1.2, 0.9 Hz, CH),
5.37 (1H, q, J ¼ 1.5, 0.9 Hz, CH), 7.10 (2H, s, HAr), 9.94 (1H, s,
CHO); 13C NMR ꢀ 22.8, 56.1, 105.2, 107.1, 116.2, 136.3, 138.2, 157.7,
191.7; IR ꢁ 1670, 1560 cmÀ1
.
2,6-Dimethoxy-4-methylethylbenzaldehyde (3d): Aldehyde 3c (0.8 g,
3.7 mmol) was dissolved in a mixture of CH3OH (15 mL) and HC(OCH3)3
(10 mL) containing a catalytic amount of NH4Cl (20 mg). The mixture
was stirred at reflux temperature under dry Ar for 4 h, then chilled to r.t.,
and Et3N (2 mL) was added dropwise. After stirring at r.t. for 10 min,

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Antibiotic Stilbenes by Reductive Metalation
1315
H2O (20 mL) was added and the mixture diluted with Et2O (20 mL).
The organic phase was separated and the aqueous phase extracted with
Et2O (3 Â 20 mL). The organic phase was washed with H2O (2 Â 20 mL),
dried (K2CO3) and the solvent evaporated to recover 0.81 g of an oil which
appearedhomogeneousbyTLCanalysis(AcOEt/Et.Petr. ¼ 7:3,Rf ¼ 0.40),
did not show any IR carbonyl stretching absorption, and was not further
characterized.
The residue was dissolved in EtOH (15 mL) and hydrogenated at r.t.
and atmospheric pressure under magnetic stirring during 5 h. The reaction
mixture was filtered, the solvent evaporated, the residue dissolved in
THF/H2SO4 2N ¼ 1:1 (10 mL) and stirred at r.t. for 2 h. The mixture was
diluted with Et2O (10 mL) and H2O (10 mL), and the organic phase was
separated. The aqueous phase was extracted with Et2O (3 Â 10 mL), and
the organic phase washed with H2O (2 Â 10 mL), sat. NaHCO3 (10 mL),
dried (Na2SO4) and the solvent evaporated. The residue was purified by
flash chromatography (AcOEt/Et. Petr. ¼ 2:8, Rf ¼ 0.43) to afford pure 3d
(0.50 g, 2.4 mmol, 65%), characterized as follows: white solid, m.p. 57ꢀC
(CH3OH); 1H NMR ꢀ 1.29 (6H, d, J ¼ 6.9 Hz, CH3), 3.66 (1H, ept,
J ¼ 7.2 Hz, CH), 3.87 (6H, s, OCH3), 7.05 (2H, s, HAr), 9.89 (1H, s,
CHO); 13C NMR ꢀ 20.0, 24.5, 55.7, 105.4, 131.8, 135.0, 158.9, 191.9;
IR ꢁ 1685, 1580 cmÀ1. Anal. calcd. for C12H16O3: C 69.20; H 7.76. Found:
C 69.08; H 7.85.
(E )-1,3-Dimethoxy-2-(1-methylethyl)-5-(2-phenylethenyl)benzene (4b):
NaH (2.8 mmol, 0.11 g of a 60% dispersion in mineral oil) was placed
under dry Ar in a two-necked flask equipped with reflux condenser and
magnetic stirrer, washed with anhydrous THF (3 Â 5 mL) and suspended
in anhydrous THF (10 mL) containing 15-crown-5 (15 mg). The mixture
was chilled to 0ꢀC and a solution of diethyl benzylphosphonate (0.64 g,
0.6 mL, 2.7 mmol) and 3d (0.50 g, 2.4 mmol) in THF (5 mL) was added
dropwise. The mixture was stirred at r.t. overnight and quenched by slow
dropwise addition of H2O (10 mL). Et2O was added (20 mL), the organic
phase was separated, and the aqueous phase extracted with Et2O
(2 Â 20 mL). The organic phase was washed with H2O (20 mL), dried
(Na2SO4), and the solvent evaporated. The residue was purified by flash
chromatography (AcOEt/Et. Petr. ¼ 1:9, Rf ¼ 0.44) to afford pure 4b
(0.53 g, 1.9 mmol, 78%), characterized as follows: colorless oil, which
solidifies upon standing, m.p. 66–68ꢀC (lit.[7] m.p. 65–66ꢀC); H NMR ꢀ
1
1.29 (6H, d, J ¼ 7.2 Hz, 2 Â CH3), 3.60 (1H, ept, J ¼ 7.2 Hz, CH), 3.84 (6H,
s, CH3O), 6.69 (2H, s, ArH), 7.05 (2H, s, CH), 7.21–7.28 (1H, m, ArH),
7.30–7.38 (2H, m, ArH), 7.47–7.54 (2H, m, ArH); 13C NMR ꢀ 20.7,
24.1, 55.7, 102.8, 124.4, 126.4, 127.5, 127.9, 128.6, 129.0,
135.8, 137.3, 158.7; IR ꢁ ¼ 1580, 1570 cmÀ1
.

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1316
Azzena, Vittoria Idini, and Pilo
ACKNOWLEDGMENT
Financial support from the University of Sassari (ex 60% funds) is
gratefully acknowledged.
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28%), afforded stilbene 4b with an overall lower yield.

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Antibiotic Stilbenes by Reductive Metalation
1317
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Mantovan, M. Eur. J. Med. Chem.—Chim. Ter. 1980, 15, 17–22.
Received in the USA April 1, 2002

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