Synthesis of 1,2,4-trimethoxybenzene and its selective functionalization at C-3 by directed metalation

Article abstract of DOI:10.1080/00397910902805598

A new and efficient strategy was developed for the preparation of 1,2,4-trimethoxybenzene (3, a powerful attractant of Euglossini bees) and its C-3 derivatives (7a-j), from vanillin (2) in 56% overall yield.

Full text of DOI:10.1080/00397910902805598

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Synthesis of 1,2,4-
Trimethoxybenzene and Its
Selective Functionalization at
C-3 by Directed Metalation
Ana P. L. Alves a , Jose Augusto B. C. Júnior a ,
Glaucia B. A. Slana a , Jari N. Cardoso a , Qiang
Wang a , Rosangela S. C. Lopes a & Claudio C. Lopes
a
a Federal University of Rio de Janeiro, Institute of
Chemistry, Department of Analytical Chemistry, Rio
de Janeiro, Brazil
Published online: 08 Sep 2009.
To cite this article: Ana P. L. Alves , Jose Augusto B. C. Júnior , Glaucia B. A.
Slana , Jari N. Cardoso , Qiang Wang , Rosangela S. C. Lopes & Claudio C. Lopes
(2009) Synthesis of 1,2,4-Trimethoxybenzene and Its Selective Functionalization at
C-3 by Directed Metalation, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:20, 3693-3709, DOI:
10.1080/00397910902805598
To link to this article: http://dx.doi.org/10.1080/00397910902805598
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Synthetic Communications1, 39: 3693–3709, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902805598
Synthesis of 1,2,4-Trimethoxybenzene
and Its Selective Functionalization at C-3
by Directed Metalation
´
Ana P. L. Alves, Jose Augusto B. C. Junior, Glaucia B. A. Slana,
Jari N. Cardoso, Qiang Wang, Rosangela S. C. Lopes, and
Claudio C. Lopes
Federal University of Rio de Janeiro, Institute of Chemistry, Department
of Analytical Chemistry, Rio de Janeiro, Brazil
Abstract: A new and efficient strategy was developed for the preparation of
1,2,4-trimethoxybenzene (3, a powerful attractant of Euglossini bees) and its
C-3 derivatives (7a–j), from vanillin (2) in 56% overall yield.
Keywords: Aromatic lithiation, directed metalation, Euglossini bees, regioselec-
tivity, 1,2,4-trimethoxybenzene
INTRODUCTION
Indol (1) is one of the N-heterocyclic compounds most widespread
among floral scents in nature, and 1,2,4-trimethoxybenzene can be found
in the volatiles of Cucurbita, Cymbidium, Hyacinthus, Pyrola, and Syringa
species.[1] The latter also can be obtained from the methylation of
1,4-dihydroxy-2-methoxybenzene by CH3I, in the presence of potassium
hydroxide (KOH).[2]
Vanillin (2) is the major component of natural vanilla, one of the
most widely used and important flavoring materials worldwide, especially
Received October 8, 2008.
Address correspondence to Claudio C. Lopes, Federal University of Rio de
Janeiro, Institute of Chemistry, Department of Analytical Chemistry, CT, Bloco
A, s. 508, Rio de Janeiro, RJ, Brazil. E-mail: claudiosabbatini@uol.com.br
3693

3694
A. P. L. Alves et al.
in the food and pharmaceutical industries. The natural source of vanilla
is the Vanilla orchids.[3]
The aim of this work is to evaluate the ability of a mixture of semio-
chemicals, called TIV (1,2,4-trimethoxybenzene, indol, and vanillin), in
attracting insects of a citrus orchard, in the county of Silva Jardim,
Rio de Janeiro, Brazil. For the preparation of the TIV mixture, we have
proposed a new low-cost synthetic route to 1,2,4-trimethoxybenzene (3).
RESULTS AND DISCUSSION
The mixture called TIV (Fig. 1) is formed by the semiochemicals indol
(1), vanillin (2), both of which were purchased from Aldrich Co., and
1,2,4-trimethoxybenzene (3), which was synthesized in our laboratory
from (2) through a low-cost and fast route (Fig. 2).
Our synthetic approach for the preparation of 3 started with the
methylation of vanillin (2) by treatment with methyl iodide (CH3I), in
the presence of K2CO3, in CH3COCH3 under reflux, to obtain 3,4-
dimethoxybenzaldehyde (4) in 95% yield.
The next step was oxidation of the carbonyl carbon of the aldehyde
(4). For this purpose, 4 was subjected to different reactional oxidation con-
ditions (Table 1), employing H2O2 or m-CPBA as the oxidant agents.[4]
The first oxidation condition (sodium hydroxide, NaOH, in H2O2),
aimed at the preparation of the phenol (6), used less severe and
more ordinary reaction conditions (Table 1, Entry 1). However, this
attempt was not adequate to yield 6. Thus, another oxidant agent was
employed, affording stronger oxidant conditions [3-chloroperbenzoic
acid (m-CPBA) in CH2Cl2 reflux)], followed by basic hydrolysis (KOH=
methanol [MeOH]) (Table 1, entry 2). It was possible now to obtain 6 in a
poor yield (only 15%, from 4). Moreover, the overall yield was 14%,
which was not adequate for our purposes. Therefore, other reactions
and experimental conditions were tried to improve the final yield.
The best result was obtained (Table 1, entry 3) when 3,4-dimethoxy-
benzaldehyde (4) was treated with m-CPBA in CH2Cl2 in a buffered
Figure 1. Semiochemicals in the TIV mixture.

1,2,4-Trimethoxybenzene and C-3 Derivatives
3695
Figure 2. Synthetic approach for the preparation of 1,2,4-trimethoxybenzene (3)
from vanillin (2).
reaction mixture with NaHCO3 to form 3,4-dimethoxyphenyl formate
(5), which was subjected to basic hydrolysis in KOH=MeOH to obtain
3,4-dimethoxyphenol (6) from 4 in 61% yield.
Finally, 6 was methylated by CH3I in K2CO3=CH3COCH3 to afford
3 in 97% yield. The overall synthetic yield of 3 was 56%, which satisfied
our aim of gettting this compound by a practical and cheap synthetic
route.[5–8]
1
All compounds were characterized through infrared (IR), H NMR,
and 13C NMR analysis.
Insects Attracted by TIV Mixture in Citrous Orchard: Preliminary
Field Experiments
McPhail traps containing the TIV mixture were installed in a domestic
citrus orchard in Bom Jesus Farm, at Silva Jardim, in the state of Rio
de Janeiro, Brazil. In this type of trap, the insects are attracted not only
Table 1. Baeyer–Villiger’s reaction yields from 3,4-dimethoxybenzaldehyde (4)
and global route yields
Yields (%)
in 6
Global yields
(%) in 3
Enters
Reagent
1
2
3
3,4-Dimethoxybenzaldehyde[12] (4)
3,4-Dimethoxybenzaldehyde (4)
3,4-Dimethoxybenzaldehyde (4)
—
15
61
—
14
56

3696
A. P. L. Alves et al.
Figure 3. Euglossine bees attracted in field experiments.
by the odour stimulus (semiochemical mixture) but also by a visual sign,
the yellow color of the trap interior. Once inside the trap, insects are not
able to escape because they fly toward the superior colorless piece and
ultimately die without food and energy.
After 7 days of exposure (Fig. 3), four species of insects were
captured and sent for identification at the University of Sao Paulo
(Departament of Biology of the Faculty of Philosophy, Sciences, and
Literature of Ribeira˜o Preto). None of the insects captured was observed
in blank traps (without TIV). In Table 2, we list the four species attrac-
ted by the TIV mixture in the preliminary test.
All insects attracted by the TIV mixture belong to the most impor-
tant genus of the Euglossini tribe: Eulaema sp. and Euglossa sp.
Euglossine bees (Apidae: Euglossini) are an important exclusively
neotropical pollinator group that are most closely related with certain
Angiosperm families. Without specifically trying to collect pollen, they
Table 2. Field experiment results
Traps
Species
Average
Total
Blanks
Eulaema nigrita Lepeletier, 1841
Euglossa pleosticta Dressler, 1982
Euglossa securigera Dressler, 1982 (sensu Moure)
Euglossa sp. aff. Sapphirina Moure, 1968
4.33
15.83
0.33
0.5
26
95
2
—
—
—
—
3

1,2,4-Trimethoxybenzene and C-3 Derivatives
3697
are able to secure pollination of species of Caesalpiniaceae, Maranthaceae,
Euphorbiaceae, Araceae, Gesneriaceae, Bignoniaceae, Orchidaceae, and
others.[8] They are known as orchid bees.
Male euglossine bees are the only pollinators of some orchids (e.g.,
Gongora, Castasctum, and Coryanthes). They are attracted to the essences
produced by these orchids’ flowers. The mechanism of attraction of these
essences is not well understood, but they may act as a sexual attractant.[9]
Euglossine bees are described as a group of brightly colored tropical
insects. Many species are green, blue, purple, gold, or red. However, in
the Eulaema generus, the insects are bigger with less metallic-colored
bright bodies. They have tongues that, in some species, may be twice
as long as the body. The long tongue allows them to reach nectar in
deep-throated tropical flowers. Many species of Eulema bees collect
nectar, pollen, and other substances from orchids.
Our mixture of semiochemicals (TIV) captured four species of
euglossine bees (Table 2): Eulaema nigrita Lepeletier (1841), Euglossa
pleosticta Dressler (1982), and Euglossa securigera Dressler (1982), and
sensu Moure and Euglossa sp. aff. Sapphirina Moure (1968).
Eulaema nigrita and Euglossa pleosticta were the most attracted spe-
cies under the tested conditions, with 21% and 75% respectively (Fig. 3).
Eulaema nigrita is an important natural pollinator of Passiflora sp.
The natural fertilization of its flowers is rare because of the autoin-
compatibility, yielding small fruits with few seeds. Pollinization in the
commercial crops of Passiflora sp. is naturally done by insects of Eulaema
and Xylocopa sp. or artificially by people.
Euglossa sp. are important in orchid pollinization. Those flowers are
cultivated for their fragrances and exotic beauty. Thus, all insects cap-
tured may have commercial importance. TIV mixture application in
orchid cultivation and Passiflora sp. crops is proposed with the aim of
increasing the population of pollinators in these areas and therefore
improving the production of flowers and fruits.
Synthesis of 1,2,4-Trimethoxybenzene C-3 Derivatives (7a–j)
The success of species attraction by the TIV mixture in a citrus orchard
and the good yields obtained in the preparation of 1,2,4-trimethoxyben-
zene encouraged the synthesis of 1,2,4-trimethoxybenzene C-3 derivatives
(Fig. 4) to evaluate their insect attractant potential for future studies.
Field studies about the use of 1,2,4-trimethoxybenzene C-3 deriva-
tives (7a–j) as semiochemicals could not be found. Therefore, an evalua-
tion of these compounds as strong candidates as insect attractants for
pest or pollinators studies seemed promising.

3698
A. P. L. Alves et al.
Figure 4. 1,2,4-Trimethoxybenzene C-3 derivatives.
Based on the experience of our research group in metalation reac-
tions using n-butyl-lithium, the study of this reaction in the preparation
of 7a–j was decided. The synthesis of 10 derivates at carbon 3, to explore
the fact that this carbon is activated by the presence of two
ortho-directing metalation groups (DoM), the methoxy in C-2 and C-4,
was proposed.
Organolithium reagents are characterized by the presence of a C–Li
covalent bond. They can act as bases or nucleophiles, because of the
difference in electronegativity between C and Li, creating a polarization
in which C is partially negative.
The most-used solvents in metalation reaction with lithium are ethyl
ether, tetrahydrofuran (THF), pentane, and hexane. In fact, the organo-
lithium reagents are found in aggregated states that depend on the type of
lithium reagent and the solvents. If the solvation of the organolithium is
low, the lithium reagent interacts more, and thus the aggregation state is
greater. However, if the solvent complexes the organolithium, the aggre-
gation state is lower, and the ionic character of the C-Li covalent bond
becomes greater. The more deoligomerized the lithium reagent, the more
reactive it is.[10]
The DoM reaction (Fig. 5) comprises the deprotonation of a site
ortho to a heteroatom-containing DMG (directed metalation group) by
a strong base, normally an alkyllithium reagent, leading to an ortho-
lithiated species (8).[11]
Figure 5. Directed metalation reaction for the preparation of 1,2,4-trimethoxy-
benzene C-3 derivatives.

1,2,4-Trimethoxybenzene and C-3 Derivatives
3699
Figure 6. Prior-coordination complex formed between the alkyllithium reagent
and the DoM of the aromatic substrate.
First, there is formation of a precoordination complex (Fig. 6)
between the alkyllithium reagent and the DoM group of the aromatic
substrate. This coordination complex is paramount to involvement of
the complexed-induced proximity effect (CIPE). Facilitated by the pro-
ximity of the lithium atom to an ortho-hydrogen on the substrate, a
lithium=ortho-H exchange occurs. The species formed, upon treatment
with electrophilic reagents, yields 1,2-disubstituted products (7).[12]
The second synthetic step of this work was the selective metalation
reaction of 3 to prepare its C-3 derivatives (7a–j). Selectivity was expected
on account of the DoMs (–OCH3) in positions 2 and 4, which directed the
metalation to position 3 preferentially relative to positions 5 and 6. Acc-
ording to Snieckus,[11] the cooperative effect of 1,3-interrelated DMGs
promotes metalation at their common site, which means position 2.
Because of the complexity of the organolithium reactions, different
experimental conditions were tried (Table 3) to establish optimum yields.
Methyl iodide was chosen as an electrophile to test conditions that could
be extrapolated to the synthesis of the other derivatives.
Table 3. Experimental conditions tested in the directed metalation reaction of
1,2,4-trimethoxybenzene using CH3I as electrophile
Organolithium
reagentsꢀ
Reaction
timeꢀꢀ(h)
yields
(7a) (%)
Enters
Solvents
1
2
3
4
5
6
s-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
Ether
Ether
Thf
Hexane
Thf
Ether
1,5
1,5
1,5
2
3
3
—
75
30
—
15
67
ꢀThere were employed 1,1,eq of the organolithium reagent and CH3I.
ꢀꢀTime of the reaction before the addition of the electrophile.

3700
A. P. L. Alves et al.
We started studying the yields of metalation with n-BuLi and s-BuLi
in our work conditions (Table 3, entries 1 and 2). Entry 1 suggests that
the presence of the methoxy groups at C-2 and C-4 of (3) may be a steric
restriction to a more hindered base in relation to its linear analog.
The results obtained with n-BuLi (entry 2) encouraged testing other
conditions to evaluate solvent effects. Therefore, ethyl ether, hexane, and
THF were used as solvents. Although n-BuLi presents hexameric struc-
ture in nonpolar hydrocarbons, which permits little, if any, directed
metalation of aromatic substrates, Slucom et al.[12] published a work in
which the directed metalation of 1,2- and 1,3-dimethoxybenzenes and
1,2,4-trimethoxybenzenes were done in this solvent, in good yields.
According to Slucom,[12] those compounds possess DMGs sufficiently
able to complex and thereby deoligomerize n-BuLi. Thus, they could
function simultaneously as both the substrate and as the catalyst. In this
way, the reagent itself would first deoligomerize the alkyllithium reagent
to a reactive dimer, and subsequently, once in this reactive form, the
aromatic reagent could react to generate
a lithiated aromatic
intermediate.[12] However, the results reported in the literature could
not be duplicated in our laboratory, when hexane was used as solvent
(Table 3, entry 4).
n-BuLi exists in a tetrameric form in diethylether, whereas a mixture
of the dimeric and tetrameric structures exist in THF. The dimer is
considered as the most reactive of the n-BuLi oligomeric forms.[12]
The yields in the reactions using THF as solvent (Table 3, entries 3
and 4) were not better than the ones obtained in the reactions using ethyl
ether. We believe that such results may be related to the fact that they are
sufficiently polar to deoligomerize alkyllithium reagents and also readily
dissolve arene substrates.[12] Thus, from those results, the conditions of
entry 2 (Table 3) to synthesize the other derivatives of 3 were adopted.
The reaction time was also analyzed but did not seem to affect the results.
All C-3 derivatives (7a–j) were prepared, and structures were
1
characterized through IR, H NMR, and 13C NMR analysis.
CONCLUSIONS
By employing a low-cost approach, 1,2,4-trimethoxybenzene (3) was
synthesized in 56% overall yield, after a study to determine optimum con-
ditions to prepare 6 from 4. Ten 1,2,4-trimethoxybenzene C-3 derivatives
(7a–j) were also prepared in excellent yield, using the metalation reaction
with n-BuLi.
The preliminary field study was conducted in a citrous orchard,
located at Bom Jesus Farm in Silva Jardim, and showed promising results

1,2,4-Trimethoxybenzene and C-3 Derivatives
3701
in attracting insects with the TIV mixture. Pollinators (orchid bees) were
captured, especially Eulaema nigrita Lepeletier (1841) and Euglossa
pleosticta Dressler (1982), both of which are important in the Passiflora
sp. crops and orchid cultivars, respectively. In this way, TIV mixtures
may be used in those crops or cultivars to increase the population of
pollinators.
A field study of the C-3 derivatives (7a–j) to evaluate their potential
as insect attractants as well as the contribution of each individual TIV
mixture constituent to attract insects are planned for future work. The
determination of the optimum proportion of each component in the
mixture is also intended.
EXPERIMENTAL
General Methods
Solvents and reagents were purchased from Vetec, Aldrich, Merck,
´
Grupo Quımica, Isotec Inc., and Acros Organics. All solvents were dried
and purified prior to use. All reactions were performed under anhydrous
conditions and were conducted in oven-dried glassware under an argon
atmosphere. Air-sensitive solutions were transferred via oven-dried
syringe needles or an oven-dried cannula under positive pressure of
argon. Ether was distilled from Na=benzophenone ketyl.
IR spectra were recorded on Magma IR-760-Nicolet spectrometer.
Fourier transform (FT)-IR spectra were taken in over KBr windows
and absorption maxima are reported in centimetersꢁl.
Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR)
spectra were recorded on Varian Gemini 200-MHz or Brucker 300-
MHz spectrometers. FT-NMR spectra were done in CDCl3 or dimethyl-
sulfoxide (DMSO)-d6. Chemical shifts (d) are reported relative to
tetramethylsilane (TMS; dTMS ¼ 0) in parts per million, and the g
constants (J) are reported in hertz. The following abbreviations were
employed for multiplicities: s (singlet), d (dublet), dd (double dublet),
dt (double triplet), q (quartet), and m (multiplet).
High-resolution mass spectra (HRMS) were taken on Atlas MS-12,
Consolidated 12–110 B, or Finnegan 400 mass spectrometers at 70 eV
at the University of California (Berkeley, USA). Where mass spectral
(MS) data are given, the peak value is immediately followed by its relative
abundance in parentheses.
Melting points were recorded on a Mel-TempII capillary melting-
point apparatus (Aldrich), and temperatures (uncorrected) are reported
in degrees C.

3702
A. P. L. Alves et al.
Chromatography
All reactions were followed by thin-layer chromatography (TLC), on
0.2 mm silica-gel 60 F254 plates (Merck). Plates were visualized by spray-
ing with 2,4-dinitrophenylhydrazine, p-anisaldehyde, or iron chloride
solutions or under ultraviolet (UV) light.
In cases where a product was purified by column chromatography,
silica-gel 60 flash chromatography was used (230–400 mesh ASTM,
Merck).
Field Experiments
Field experiments were carried out at Bom Jesus Farm (off interstate BR
101, Km 35, Silva Jardim county), Rio de Janeiro. The baited traps were
placed February 1–7, 2004, and removed after 7 days.
Indol (1), vanillin (2), and 1,2,4-trimethoxybenzene (3) are all volatile
substances, known as flower semiochemicals.[1] A mixture of these chemi-
cals, named the TIV mixture, was tested in a citrus orchard (about
120 mꢂ5 m), in a preliminary study for evaluating the insect responses to
baited traps (McPhail type one, Biocontrole, Brazil). 1,2,4-Trimethoxy-
benzene (3) was synthesized in our laboratory from vanillin (2), and indol
(1) and vanillin (2) were purchased from Vetec (Brazil).
The traps with 300 mg of TIV were fixed at 1.5 m high in orange
trees. The mixture was used at a dosage of 100 mg of each single chemical
per trap. Control traps received no TIV. Distance between traps was at
least 5 m. The average temperature was 35ꢃC during 7 days of field
experiments.
After the 7-day field test, traps were sent to the University of Sao
Paulo, where insect species were identified.
Synthesis of 1,2,4-Trimethoxybenzene (3) from Vanilin (2)
Preparation of 3,4-Dimethoxybenzaldehyde (4)
In a three-neck, round-bottom flask with a reflux condenser, a suspen-
sion of vanilin (500 mg, 3.29 mmol, mol. wt. 152.00 g=mol) and K2CO3
(500 mg 3.62 mmol mol. wt. 138.21 g=mol) in anhydrous CH3COCH3
(40 mL) was stirred at 40–45ꢃC, under an argonium atmosphere. After
1 h, CH3I (716 mg, 0.32 mL, 4.94 mmol, mol wt. 144.92 g=mol, d ¼
2.26 g=mL) was added dropwise, and the resulting mixture was refluxed
for 7 h. The solvent was then removed under reduced pressure, and the

1,2,4-Trimethoxybenzene and C-3 Derivatives
3703
resulting solid was poured into HCl 5% (10 mL) and extracted with
EtOAc (3ꢂ20 mL). The organic layer was then washed with brine, dried
over Na2SO4, evaporated to dryness, and purified by silica-gel chromato-
graphy (5–20% EtOAc=hexanes to yield 3,4-dimethoxybenzaldehyde (4)
as a pale yellow solid (518.75 mg; 95%), mp 43–45ꢃC; IR (KBr, cmꢁ1):
3077, 3019, 2999, 2920, 2849, 2765 (O¼C-H), 1.686 (C¼O), 1275 (C-O-
C), 1018 (C-O-C), 802; 1H NMR (CDCl3, 200 MHz) d: 9.84 (s, 1H,
COH), 7.48–7.39 (m, 2H, H-Ar), 6.97 (d, J ¼ 8 Hz, 1H, H-Ar), 3.96 (s,
3H, OCH3), 3.93 (s, 3H, OCH3); 13C NMR (CDCl3, 50 MHz) d: 191.0
(C¼O), 154.6 (C-OCH3), 149.7 (C-OCH3), 130.2 (C-CHO), 127.0 (H-
Car), 110.5 (H-Car), 109.0 (H-Car), 56.3 (OCH3), 56.1 (OCH3).
Preparation of 3,4-Dimethoxyphenol (6)
In a three-neck, round-bottom flask with a reflux condenser, m-CBPA
70% (3.6 g, 20.00 mmol, mol. wt. 172.50 g=mol) and NaHCO3 (0.58 g,
7.00 mmol, mol. wt. 84.00 g=mol) were added with stirring to a solution
of 3,4-dimethoxybenzaldehyde (4) (1.66 g, 10.00 mmol, mol. wt. 166.00 g=
mol) in anhydrous CH2Cl2 (50 mL). The mixture was allowed to reflux
for about 10–15 h. Most CH2Cl2 was separated by distillation, and the
resulting material was dissolved in EtOAc (50 mL). The organic layer
was poured into NaHSO3 10% (3ꢂ15 mL), washed with brine, dried over
Na2SO4, and evaporated to dryness to yield 3,4-dimethoxyphenyl
formate (5) as a pale red oil (83.5%); IR (KBr, cmꢁ1): 3087, 3074,
3006, 2959, 2939, 2913, 2875, 2838 (O¼C-H), 1738 (C¼O), 1266 (C-O-
C), 1026 (C-O-C), 867; 1H NMR (CDCl3, 200 MHz) d: 8.29 (s, 1H,
OOC-H), 6.86 (d, 1H, H-Ar), 6.67 (s, 2H, broad, H-Ar), 3.87 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3); 13C NMR (CDCl3, 50 MHz) d: 159.7
(OCOH), 149.6 (C-OCH3), 147.3 (C-OCHO), 143.6 (C-OCH3), 112.4
(H-Car), 111.3 (H-Car), 105.3 (H-Car), 56.2 (OCH3), 56.1 (OCH3).
Afterwards, the crude product (5) was dissolved in MeOH (5 mL)
under an N2 atmosphere. Then, a solution of KOH 10% (10 mL) was
added dropwise, allowing basic hydrolysis of 5. The mixture was poured
into HCl 5% (5–15 mL), extracted with EtOAc (3ꢂ15 mL), washed with
brine (3ꢂ10 mL), dried over Na2SO4, and evaporated to dryness to yield
3,4-dimethoxyphenol (6) as a red oil (61%, from 15); IR (KBr, cmꢁ1):
3396 (O-H), 3087, 3044, 3003, 2959, 2938, 2835, 1224 (C-O-C), 1025
1
(C-O-C), 835; H NMR (CDCl3, 200 MHz) d: 6.73 (d, J ¼ 8 Hz, 1H,
H-Ar), 6.47 (s, 1H, H-Ar), 6.36 (d, J ¼ 8 Hz, 1H, H-Ar), 3.81 (s, 3 H,
OCH3), 3.81 (s, 3 H, OCH3); 13C NMR (CDCl3, 50 MHz) d: 150.4
(C-OCH3), 150.0 (C-OCH3), 143.2 (C-OH), 112.7 (H-Car), 106.0
(H-Car), 100.8 (H-Car), 56.7 (OCH3), 55.9 (OCH3).

3704
A. P. L. Alves et al.
Preparation of 1,2,4-Trimethoxybenzene (3)
In a three-neck, round-bottom flask with a reflux condenser, a suspen-
sion of crude 3,4-dimethoxyphenol (6) (500 mg, 3.29 mmol, mol. wt.
152.00 g=mol) and K2CO3 (986.7 mg, 7.14 mmol, mol wt. 138.21 g=mol)
in anhydrous CH3COCH3 (30 mL) was stirred at 40–45ꢃC, under an
argonium atmosphere. After 1 h, CH3I (1.41 g, 0.62 mL, 9.74 mmol,
mol wt. 144.92 g=mol, d ¼ 2.26 g=mL) was added dropwise, and the
resulting mixture was refluxed for 7 h.
The solvent was then removed under reduced pressure, and the
resulting oil was poured into HCl 5% (10 mL) and extracted with EtOAc
(3 ꢂ 20 mL). The organic layer was then washed with brine, dried over
Na2SO4, evaporated to dryness, and purified by silica-gel chromatogra-
phy (5% EtOAc=hexanes) to yield 1,2,4-trimethoxybenzene (3) as an oil
(97%); IR (KBr, cmꢁ1): 3081, 2998, 2938, 2908, 2834, 1230 (C-O-C),
1
1027 (C-O-C), 834; H NMR (CDCl3, 200 MHz) d: 6.79 (d, J ¼ 8 Hz,
1H, H-Ar); 6,52 (d, J ¼ 3 Hz, 1H, H-Ar); 6.39 (dd, J ¼ 3 Hz, J ¼ 8 Hz, 1
H, H-Ar), 3.86 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.77 (s, 3H,
OCH3); 13C NMR (CDCl3, 50 MHz) d: 154.4 (C-OCH3), 150.0 (C-
OCH3), 143.6 (C-OCH3), 112.0 (H-Car), 103.0 (H-Car), 100.5 (H-Car),
56.6 (OCH3), 55.9 (OCH3), 55.8 (OCH3); HRMS m=z (%): 168.078550
(68.4). Calc. for C10H14O3: 168.078644.
Synthesis of 1,2,4-Trimethoxybenzene C-3 Derivatives (7a–j)
General Procedure
n-Butyl lithium in hexanes 1.1 eq, (2.5 M) was added dropwise to a
solution of 1,2,4–trimethoxybenzene (5) (400 mg, 0.36 mL, 2.38 mmol,
mol wt. 168.19 g=mol; d ¼ 1.126 g=mL) in anhydrous ether (15 mL) at
ꢁ10ꢃC under an argonium atmosphere. A white precipitate was
formed. The reaction mixture was stirred additionally for 1.5 h at
room temperature. Then, 1.1 eq of electrophilus (2.62 mmol) dissolved
in anhydrous ether (5 mL) was added dropwise at ꢁ10ꢃC under an
argonium atmosphere, and the mixture was allowed to stir overnight.
The reaction was extracted with EtOAc (3 ꢂ 15 mL) and saturated
NH4Cl solution (3 ꢂ 10 mL) or 10% NaHSO3 solution (derivatives 7c
and 7h) until complete neutralization. The total organic layer was
washed with brine (3 ꢂ 10 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to obtain a crude
residue, which was subjected to silica-gel chromatography (EtOAC=
hexanes).

1,2,4-Trimethoxybenzene and C-3 Derivatives
3705
Preparation of 1,2,4-Trimethoxy-3-methylbenzene (7a)
From 3 and CH3I (328 mg, 0.15 mL, 2.62 mmol, mol. wt. 144.92 g=mol;
d ¼ 2.26 g=mL) to yield 7a as a white solid, after silica-gel chromatogra-
phy (EtOAc 5%–hexanes): 325.00 mg, 75%; mp: 29–31ꢃC; IR (KBr,
1
cmꢁ1): 2995, 2937, 2859, 2833, 1257 (C-O-C), 1026 (C-O-C); H NMR
(CDCl3, 200 MHz) d: 6.71 (d, J ¼ 8 Hz, 1H, H-Ar), 6.55 (d, J ¼ 8 Hz,
1H, H-Ar), 3.83 (s, 3, OCH3), 3.81 (s, 3 H, OCH3), 3.79 (s, 3H,
OCH3), 2.18 (s, 3H, CH3); 13C NMR (CDCl3, 50 MHz) d: 152.6
(C-OCH3), 148.3 (C-OCH3), 147.3 (C-OCH3), 121.3 (C-CH3), 109.4
(H-Car), 105.3 (H-Car), 60.5 (OCH3), 56.3 (OCH3), 56.0 (OCH3), 9.1
(CH3); HRMS m=z (%): 182.094154 (100.0). Calc. for C10H14O3:
182.094294.
Preparation of 2,3,6-Trimethoxybenzaldehyde (7b)
From 3 and dimethylformamide (192 mg; 0.20 mL, 2.62 mmol, mol. wt.
73.09 g=mol; d ¼ 0.95 g=mL) to yield 7b as an orange oil, after gradient
silica-gel chromatography (EtOAc 5–20%=hexanes): 285.00 mg; 61%;
IR (KBr, cmꢁ1): 3094, 3001, 2941, 2838, 2765 (O¼C-H), 1692 (C¼O),
1
1260 (C-O-C), 1069 (C-O-C); H NMR (CDCl3, 200 MHz) d: 10.43 (s,
1H, C-COH), 7.07 (d, J ¼ 10 Hz, 1H, H-Ar), 6.63 (d, J ¼ 10 Hz, 1H, H-
Ar), 3.91 (s, 3H, OCH3), 3.83 (s, 6H, OCH3); 13C NMR (CDCl3,
50 MHz) d: 189.8 (C¼O), 155.0 (C-OCH3), 152.2 (C-OCH3), 146.9 (C-
OCH3), 119.8 (C-CHO), 119.3 (H-Car), 106.5 (H-Car), 62.1 (OCH3),
56.8 (OCH3), 56.3 (OCH3); HRMS m=z (%): 196.073196 (100.0). Calc.
for C10H12O4: 196.073559.
Preparation of 2-Bromo-1,3,4-trimethoxybenzene (7c)
From 3 and CBr4 (869 mg, 2.62 mmol, mol. wt. 331.65 g=mol) to yield 7c
as yellow solid, after silica-gel chromatography (EtOAc 5%-hexanes):
527 mg; 89.6%; mp: 69–71ꢃC; IR (KBr, cmꢁ1): 3092, 3061, 3004, 2955,
1
2934, 2907, 2870, 2833, 1256 (C-O-C), 1040 (C-O-C), 651 (C-Br); H
NMR (CDCl3, 200 MHz) d: 6.83 (d, J ¼ 10 Hz, 1H, H-Ar), 6.62 (d,
J ¼ 10 Hz, 1H, H-Ar), 3.87 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.84
(s, 3H, OCH3); 13C NMR (CDCl3, 50 MHz) d: 151.1 (C-OCH3),
148.1 (C-OCH3), 147.9 (C-OCH3), 111.7 (H-Car), 108.4 (C-Br), 106.8
(H-Car), 60.6 (OCH3), 56.9 (OCH3), 56.8 (OCH3); HRMS m=z (%):
245.988557 (100.0), 247.986838 (94.5). Calc. for C9H11O3Br:
245.988119, 247.987109.

3706
A. P. L. Alves et al.
Preparation of 2,3,6-Trimethoxybenzoic Acid (7d)
From 3 and solid CO2 (excess) to yield 7d as a white solid, after acid–
base extraction: (406.20 mg; 81%); mp: 143–145ꢃC; IR (KBr, cmꢁ1):
3300–2500 (broad, O-H), 3020, 3004, 2979, 2964, 2945, 2843, 1724
(C¼O), 1253 (C-O-C), 1061 (C-O-C); 1H NMR (DMSO-d6,
200 MHz) d: 7.01 (d, J ¼ 10 Hz, 1H, H-Ar), 6.73 (d, J ¼ 10 Hz, 1H,
H-Ar), 3.76 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.70 (s, 3H,
OCH3); 13C NMR (CDCl3, 50 MHz) d: 166.8 (COOH), 149.8
(C-OCH3), 146.9 (C-OCH3), 145.8 (C-OCH3), 121.1 (C-COOH),
114.2 (H-Car), 107.2 (H-Car), 61.3 (OCH3), 56.7 (OCH3), 56.5
(OCH3); HRMS m=z (%): 212.068211 (100.0). Calc. for C10H12O5:
212.068474.
Preparation of Trimethyl(2,3,6-trimethoxyphenyl)silane (7e)
From 3 and chlorotrimethylsilane 98% (285 mg, 0.34 mL, 2.62 mmol,
mol. wt. 108.64 g=mol; d ¼ 0.856 g=mL) to yield 7e as a pale yellow
oil, after silica-gel chromatography (EtOAc 5%–hexanes): 521.70 mg,
91.20 %; IR (KBr, cmꢁ1): 3073, 2952, 2939, 2900, 2832, 1463 (Si-CH3),
1
1249 (C-O-C), 1089 (C-O-C); H NMR (CDCl3, 200 MHz) d: 6.90 (d,
J ¼ 8 Hz, 1H, H-Ar), 6.56 (d, J ¼ 8 Hz, 1H, H-Ar), 3.84 (s, 3H,
OCH3), 3.82 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 0.350 (s, 3H, CH3),
0.333 (s, 3H, CH3), 0.283 (s, 3H, CH3); 13C NMR (CDCl3, 50 MHz)
d: 158.6 (C-OCH3), 154.6 (C-OCH3), 147.0 (C-OCH3), 121.2 (Si-Car),
114.54 (H-Car), 105.4 (H-Car), 60.9 (OCH3), 56.3 (OCH3), 55.6
(OCH3), 1.4 (CH3); HRMS m=z (%): 240.118123 (100.0). Calc. for
C12H20O3Si: 240.118173.
Preparation of 3-D-1,2,4-Trimethoxybenzene (7f)
From 3 and D2O (excess) to yield 7f as a pale yellow liquid, after silica-gel
chromatography (EtOAc 5%-hexanes): 221.20 mg, 55%; IR (KBr, cmꢁ1):
1
3081, 2998, 2938, 2908, 2834, 1229 (C-O-C), 1026 (C-O-C); H NMR
(CDCl3, 200 MHz) d: 6.78 (d, J ¼ 8 Hz, 1H, H-Ar), 6.39 (d, J ¼ 8 Hz,
1H, H-Ar), 3.85 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3); 13C NMR (CDCl3, 50 MHz) d: 154.3 (C-OCH3), 150.0 (C-
OCH3), 143.5 (C-OCH3), 111.9 (H-Car), 103.0 (H-Car), 100.2 (C-D),
56.5 (OCH3), 55.9 (OCH3), 55.7 (OCH3). HRMS m=z (%): 169.08520
(10.5). Calc. for C9H11DO3: 169.084921.

1,2,4-Trimethoxybenzene and C-3 Derivatives
3707
Preparation of N,N-Diethyl-2,3,6-trimethoxybenzamide (7g)
From 3 and diethylcarbamic chloride (355 mg, 0.33 mL, 2.62 mmol, mol.
wt. 135.59 g=mol; d ¼ 1.070 g=mL) to yield 7 g as a yellow solid, after gra-
dient silica-gel chromatography (EtOAc 10–50%=hexanes): 381.3 mg,
60%; mp: 73–75ꢃC, IR (KBr, cmꢁ1): 3100, 3068, 2980, 2970, 2938,
2906, 2839, 1633 (C¼O), 1258 (C-O-C), 1061 (C-O-C); 1H NMR
(CDCl3, 300 MHz) d: 6.83 (d, J ¼ 9 Hz, 1H, H-Ar), 6.58 (d, J ¼ 9 Hz,
1H, H-Ar), 3.86 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 3.60 (q, J ¼ 7 Hz, 2H, CH2), 3.14 (q, J ¼ 5,4 Hz, J ¼ 1,8 Hz, 2H,
CH2), 1.25 (t, J ¼ 7 Hz, 3H, CH3), 1.03 (t, J ¼ 7 Hz, 3H, CH3); 13C
NMR (CDCl3, 75 MHz) d: 165.5 (C¼O), 149.6 (C-OCH3), 146.8
(C-OCH3), 145.6 (C-OCH3), 121.9 (C-CON-), 112.3 (H-Car), 105.9
(H-Car), 61.3 (OCH3), 56.1 (OCH3), 55.8 (OCH3), 42.6 (CH2), 38.5
(CH2), 13.6 (CH3), 12.6 (CH3); HRMS m=z (%): 267.146886 (100.0).
Calc. for C14H21O4N: 267.147058.
Preparation of Methyl 2,3,6-Trimethoxybenzoate (7h)
From 3 and methyl chroloformate (247 mg, 0.20 Ml, 2.62 mmol, mol. wt.
94.5 g=mol; d ¼ 1.223 g=mL) to yield 7h as a white solid, after gradient
silica-gel chromatography (EtOAc 20–40%=hexanes): (296.00 mg, 55%);
mp: 50–53ꢃC; IR (KBr, cmꢁ1): 3104, 3068, 3015, 2987, 2970, 2948,
2841, 1735 (C¼O), 1261 (C-O-C), 1061 (C-O-C); 1H NMR (CDCl3,
400 MHz) d: 6.88 (d, J ¼ 9 Hz, 1H, H-Ar), 6.59 (d, J ¼ 9 Hz, 1H,
H-Ar), 3.92 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.82 (s, 3H, OCH3),
3.78 (s, 3 H, OCH3); 13C NMR (CDCl3, 100 MHz) d: 166.44 (C¼O),
150.4 (C-OCH3), 146.9 (C-OCH3), 146.8 (C-OCH3), 119.1 (C-COCH3),
114.3 (H-Car), 106.1 (H-Car), 61.4 (OCH3), 56.5 (OCH3), 56.2 (OCH3),
52.4 (CH3); HRMS m=z (%): 226.084114 (100.0). Calc. for C11H14O5:
226.084124.
Preparation of 2-Allyl-1,3,4-trimethoxybenzene (7i)
From 3 and allyl bromide (317 mg, 0.22 mL, 2.62 mmol, mol. wt. 120.98 g=
mol; d ¼ 1.43 g=mL) to yield 7i as a pale yellow liquid, after gradient
silica-gel chromatography (EtOAc 5–70%=hexanes): 173.30 mg, 35%; IR
(KBr, cmꢁ1): 3077, 2997, 2976, 2938, 2907, 2833, 1256 (C-O-C), 1068
1
(C-O-C); H NMR (CDCl3, 300 MHz) d: 6.75 (d, J ¼ 9 Hz, 1H, H-Ar),
6.57 (d, J ¼ 9 Hz, 1H, H-Ar), 6.09–5.85 (m, 1 H, -CH¼), 5.07–4.93 (m, 2
H, ¼CH2), 3.83 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.78 (s, 3H,

3708
A. P. L. Alves et al.
OCH3), 3.47–3.41 (dt, J ¼ 1,6 Hz, J ¼ 3 Hz, 2 H, CH2); 13C NMR (CDCl3,
75 MHz) d: 152.0 (C-OCH3), 147.8 (C-OCH3), 147.0 (C-OCH3), 136.9
(-CH¼), 122.9 (C-allyl), 114.3 (¼CH2), 110.0 (H-Car), 105.4 (H-Car),
60.7 (OCH3), 56.0 (OCH3), 55.9 (OCH3), 28.0 (Ar-CH2-); HRMS m=z
(%): 208.109710 (100.0). Calc. for C12H16O3: 208.109945.
Preparation of 2,3,6-Trimethoxyphenylboronic Acid (7j)
From 3 and trimethylborate (272 mg, 0.30 mL, 2.62 mmol, mol. wt.
103.91 g=mol; d ¼ 0.915 g=mL) 7j was obtained as an oil, after gradient
silica-gel chromatography (EtOAc 30–50%=hexanes): (306.30 mg,
60.7%); IR (KBr, cmꢁ1): 3474, 3088, 2998, 2942, 2838, 1329 (B-O),
1
1251 (C-O-C), 1087 (C-O-C); H NMR (CDCl3, 400 MHz) d: 6.98 (d,
J ¼ 9 Hz, 1H, H-Ar), 6.66 (d, J ¼ 9 Hz, 1 H, H-Ar), 3.92 (s, 3H, OCH3),
3.86 (s, 3H, OCH3), 3.83 (s, 3H, OCH3); 13C NMR (CDCl3, 100 MHz)
d: 158.0 (C-OCH3), 154.9 (C-OCH3), 146.7 (C-OCH3), 116.0 (H-Car),
106.4 (H-Car), 61.5 (OCH3), 56.2 (OCH3), 56.1 (OCH3); HRMS m=z
(%): 212.085909 (100.0). Calc. for C9H13O5B: 212.085604.
ACKNOWLEDGMENTS
We thank CAPES, CNPQ, FAPERJ, and FUJB for financial support
and also Qiang Wang, a Postdoctoral student in Clayton H. Heathcock’s
research group, Department of Chemistry, University of California
Berkeley, USA, for personal contributions.
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