Competition of substituents for ortho direction of metalation of veratric acid

Article abstract of DOI:10.1016/j.tet.2008.08.086

LTMP (5 equiv) metalates randomly veratric acid (1). Under external quench conditions, the thermodynamically more stable lithium 2-lithio-3,4-dimethoxybenzoate (2) reacts with a variety of electrophiles to give versatile building units that are not easily accessible by conventional means. Under in situ quench conditions (LTMP/TMSCl), a reversal of regioselectivity is observed and 6-trimethylsilyl-3,4-dimethoxybenzoic acid (10) is formed predominantly.

Full text of DOI:10.1016/j.tet.2008.08.086

Tetrahedron 64 (2008) 10552–10557
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Competition of substituents for ortho direction of metalation of veratric acid
,
Nguyet Trang Thanh Chau a b, Thi Huu Nguyen a, Anne-Sophie Castanet a, Kim Phi Phung Nguyen b,
,
Jacques Mortier a
*
a
´
´
´
´
´
Universite du Maine and CNRS, Unite de Chimie Organique Moleculaire and Macromoleculaire (UMR 6011), Faculte des Sciences, Avenue Olivier Messiaen,
72085 Le Mans Cedex 9, France
b
´
Universite´ de Ho Chi Minh Ville, Ecole des Sciences Naturelles, Laboratoire de Chimie Organique, 227 Nguyen van Cu, Arrondissement 5, Ho Chi Minh Ville, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2008
Received in revised form 26 August 2008
Accepted 27 August 2008
Available online 4 September 2008
LTMP (5 equiv) metalates randomly veratric acid (1). Under external quench conditions, the thermody-
namically more stable lithium 2-lithio-3,4-dimethoxybenzoate (2) reacts with a variety of electrophiles
to give versatile building units that are not easily accessible by conventional means. Under in situ quench
conditions (LTMP/TMSCl), a reversal of regioselectivity is observed and 6-trimethylsilyl-3,4-dimethox-
ybenzoic acid (10) is formed predominantly.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
ortho-Lithiation
Organolithiums
Benzoic acids
1. Introduction
for the synthesis of HIV protease inhibitors,8 for the preparation of
analogs of quercetin9 and gossypol.10,11 2-Chloro-3,4-dimethoxy-
It is well known that certain substituents containing hetero-
atoms are able to promote the lithiation of an aromatic ring at
the ortho position (ortho-lithiation) by hydrogen–metal exchange
with an alkyllithium reagent.1,2 The effect of the heteroatom has
been explained in terms both of increased intrinsic acidity of the
ortho proton and of coordination of the metalating agent with
consequent enhancement of its ability to abstract the ortho
proton.2,3
The directed metalation group CO2H increases the discrimina-
tion between ortho positions and favors metalation over
nucleophilic addition reactions to the aromatic nucleus.4 We have
recently described its synthetic utility by demonstrating a series of
regioselective reactions derived from the competition of halo-
benzoic acids,5 anisic acids,6 and biphenyl carboxylic acids7 with
organolithiums and superbases.
benzoicacid isa core buildingunit for thesynthesis of, interalia, urea
inhibitors of protein kinases such as the mitogen-activated protein
kinases,12 analogs of lamellarin,13 and arylpiperazine-benzoylamide
derivatives of pharmaceutical interest.14 In the prior art, 2-
substituted-3,4-dimethoxybenzoic acids were prepared by de-
manding classical and poorly regioselective multisteps sequences in
low overall yield.15 ortho-(Methoxy)aryloxazolines react with
organolithium or Grignard reagents to give 2-substituted de-
rivatives resulting from the nucleophilic methoxy displacement,16
whereas meta-(methoxy)aryloxazolines are deprotonated at the C-2
position by n-BuLi.17 Nevertheless these transformations require
laborious protection and deprotection steps torestorethe carboxylic
acid moiety.
2. Results and discussion
Herein we record details of our investigations on the metalation
of veratric acid (1). As this article will demonstrate, the ‘in situ
quench protocol’ provides a powerful alternative to the stepwise
reaction. We describe methodological aspects related to the prepa-
ration of contiguously 2-substituted-3,4-dimethoxybenzoic acids,
which have found wide uses in many areas of pesticidal, pharma-
ceutical, and materials chemistry as versatile intermediates. For
instance, 3,4-dimethoxy-2-methylbenzoic acidis akeyintermediate
General conditions were chosen on the basis of preliminary
experiments with different bases (Scheme 1 and Table 1). Veratric
acid (1) did not undergo any detectable metalation when LDA
was used in excess (5 equiv) in THF at 0 ꢀC (entry 1). The reaction
was sluggish even at 66 ꢀC (entry 2). 3,4-Dimethoxy-2-methyl-
benzoic acid (5) was prepared in only 9% yield after addition of
iodomethane at 40 ꢀC. So we turned to the more basic lithium
2,2,6,6-tetramethylpiperidide (LTMP). The pKa values for diiso-
propylamine and tetramethylpiperidine in THF are, respectively,
35.7 and 37.3.18 A yield of 44% was obtained with 2.2 equiv of the
latter base (entry 3).
* Corresponding author. Tel.: þ33 243 833 336; fax: þ33 243 833 902.
E-mail address: jacques.mortier@univ-lemans.fr (J. Mortier).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.086

N.T.T. Chau et al. / Tetrahedron 64 (2008) 10552–10557
10553
CO2Li
CO2H
1) EX
2) HCl
Li
OMe
E
OMe
OMe
OMe
3
6 E = Me (0%)
9 E = TMS (8%)
COs-Bu
CO2H
Et
CO2H
TMS
CO2H
E
CO2Li
CO2H
2
TMS
Li
base
THF
1) EX
6
5
OMe
2) HCl
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
1
11
12
13
2
5 E = Me (64%)
8 E = TMS (6%)
EX = MeI, Me3SiCl
CO2Li
CO2H
Li
E
1) EX
2) HCl
OMe
OMe
OMe
OMe
4
7
E = Me (0%)
10 E = TMS (52%)
Scheme 1. Metalation of veratric acid (1).
Optimization of the reaction conditions for the formation of 5
showed that the best yield thereof (64%) was obtained when
metalation was carried out with 4 equiv of LTMP in THF at 0 ꢀC, after
in situ formation of the lithium salt of 1 with 1 equiv of n-BuLi at
ꢁ78 ꢀC, followed by addition of MeI and gentle warming at 40 ꢀC
(external quench, entry 4). Since 2-ethyl-3,4-dimethoxybenzoic
acid (11) that arises from the lateral metalation of 5 was also
formed under these conditions,19 the yield of aromatic metalation
is the combination of the yields of 5 and 11 (91%). The yield of 5 did
not improve when 2 was added slowly to MeI in THF at 0 ꢀC (reverse
addition).20
The in situ quench (ISQ) protocol,21 in which the acid 1 was
added to a solution containing LTMP (3 equiv) and TMSCl (3 equiv)
at ꢁ78 ꢀC gave a mixture of 2-trimethylsilyl-3,4-dimethoxybenzoic
acid (8) and 6-trimethylsilyl-3,4-dimethoxybenzoic acid (10) (entry
5). With 5 equiv of LTMP, 10 was formed predominantly (8/9/10,
Table 1
Metalation of veratric acid (1) with strong bases
Entry
Conditionsb,c
Yielda (%)
C-2
0
C-5
0
C-6
0
Others
1
2
3
4
(1) LDA (5 equiv), 0 ꢀC
d
(2) MeI, 0 ꢀC/40 ꢀ
C
(1) LDA (5 equiv), 66 ꢀ
(2) MeI, 40 ꢀ
(1) LTMP (2.2 equiv), 0 ꢀ
C
9 [5]
0
0
0
0
0
0
d
C
C
44 [5]
64 (40
<3 [11]
27 [11]
(2) MeI, 0 ꢀC/40 ꢀ
C
(1) n-BuLi (1 equiv), ꢁ78 ꢀ
C
*
[5])
(2) LTMP (4 equiv), 0 ꢀ
(3) MeI, 0 ꢀC/40 ꢀ
C
C
5
6
7
LTMP (3 equiv), TMSCl (3 equiv) (ISQ), ꢁ78 ꢀC/rt
15 [8]
6 [8]
0
8 [9]
0
15 [10]
52 (20* [10])
3 [10]
<3 [12]
34 (10* [12])
d
LTMP (5 equiv), TMSCl (5 equiv) (ISQ), ꢁ78 ꢀC/rt
(1) LTMP (5 equiv), 0 ꢀ
C
35 (15* [8])
21 [5]
0
(2) TMSCl (5 equiv), 0 ꢀC/rt
(1) s-BuLi/TMEDA (5 equiv), ꢁ78 ꢀC/ꢁ30 ꢀ
(2) MeI, ꢁ30 ꢀC/rt
8
C
C
6 [6]
0
35 [7]
0
22 [13]
22 [13]
d
9
(1) s-BuLi/TMEDA (2.2 equiv), ꢁ30 ꢀ
(2) MeI, ꢁ30 ꢀC/rt
C
10
(1) n-BuLi/t-BuOK (4 equiv), ꢁ78 ꢀC/ꢁ50 ꢀ
22 [5]
51 [6]
17 [7]
(2) MeI, ꢁ78 ꢀC/rt
Yields and product ratios were determined by 1H NMR after acidification of the crude reaction mixture and extraction with ether. Products 8, 10–13 were isolated by
a
chromatography (cyclohexane/ethylacetate 7:3). Isolated yields are followed by an asterisk (*).
b
Reactions were carried out in THF. The base was allowed to react with 1 for 2 h. External quench (EQ) technique except ortherwise noted. In situ quench (ISQ): the acid 1
was added to a solution of LTMP and TMSCl in THF at ꢁ78 ꢀC. Hydrolysis (2 M HCl) was carried out at rt.
c
Acids 5–7 are known in the literature. (5): see Ref. 28; (6): Borchardt, R. T.; Bhatia, P. J. Med. Chem. 1982, 25, 263–271; (7): Wu, T-C.; Rieke, R. D. J. Org. Chem. 1988, 53, 2378–
2381.

10554
N.T.T. Chau et al. / Tetrahedron 64 (2008) 10552–10557
CO2H
CO2H
TMS
CO2Li
Li
CO2Li
CO2H
Me
0.36 ppm
0.34 ppm
TMS
TMS
Li
Me
Me
7.19 ppm H5
OMe
7.13 ppm H5
OMe
OMe
OMe
O
OMe
OMe
OMe
O
s-Bu
A
OMe
Me
Li
3.97 ppm
3.90 ppm
15
16
S
10
12
Figure 1.
Figure 2.
6:8:52 ratio, entry 6), along with an appreciable amount of the
disilylated product 12 (34%). A reversal of regioselectivity was ob-
served when TMSCl was added to the preformed dianion (8/9/10,
35:0:3 ratio, entry 7). Proof for the location of the TMS groups of 10
and 12 was gathered by the NOESY technique (Fig. 1). For 10, the
hydrogen H-5 situated at 7.19 ppm shows clear interactions with
the methoxy group at 3.97 ppm as well as with the TMS group at
0.36 ppm. Therefore the TMS group of 10 is located in the position
ortho to the carboxylate (C-6). The carboxylate of 12 is flanked by
two TMS groups since the hydrogen H-5 (7.13 ppm) shows NOESY
interactions with the methoxy group at 3.90 ppm and the TMS
group at 0.34 ppm.
These results can be rationalized as follows. The fact that the
deprotonation of 1 by LTMP/TMSCl is not regioselective under ISQ
conditions (entries 5 and 6) strongly suggests that the three dia-
nions 2–4 are formed. Under similar conditions, we have showed
previously that reaction of meta-anisic acid provides a 75% yield of
2-trimethylsilyl-3-methoxybenzoic acid.6a
5-Lithio- and 6-lithio-3,4-dimethoxybenzoates (3 and 4), by
a protonation/deprotonation sequence involving 2,2,6,6-tetrame-
thylpiperidine (TMP)/LTMP, isomerize to the thermodynamically
more stabledless basicd2-lithio isomer 2 under standard external
quench conditions (entries 2–4, Scheme 2). The dianion 2 remains
indefinitely stable even in refluxing THF (þ66 ꢀC). After MeI trap-
ping, 3,4-dimethoxy-2-methylbenzoic acid (5) is formed as the sole
product.
THF at ꢁ78 ꢀC followed by addition of MeI at ꢁ30 ꢀC gave a mixture
of 5–7 (21:6:35, entry 8). Veratric acid (1) was not metalated at all
upon treatment with 2.2 equiv of s-BuLi/TMEDA (entry 9) pre-
sumably because the p-electrons of the methoxy groups coordinate
strongly with the second equivalent of base, leading to a complex of
the type A.22 The undesired ketone 13 resulting from the nucleo-
philic addition of s-BuLi to the carboxylate was also formed.23
Superbases preferentially attack the inductively activated aro-
matic position next to the most electronegative heteroatom and/or
the most acidic position available.24 Addition of 1 to 4 equiv of
preformed LICKOR made of equimolecular amounts of n-butyl-
lithium and potassium tert-butoxide,25 followed by quench with
iodomethane (0 ꢀC/40 ꢀC) provided the acids 5, 6, and 7 (22:51:17
ratio, entry 10). Metalation of 1 with 4 equiv of LICKOR at 60 ꢀC in
benzene failed.7a,26
According to the optimized conditions found at entry 4 (Table 1),
the lithio benzoate 2 also reacted, to give the expected ortho-
substituted products, with sundry other electrophilic reagents,
which included deuterium oxide, iodoethane, hexachloroethane,
1,2-dibromotetrachloroethane, iodine, dimethyl disulfide, carbon
dioxide, DMF, benzaldehyde, phenylisocyanate, and dioxygen (Ta-
ble 2). The substituted veratric acids thus obtained are versatile
materials for organic synthesis (vide supra).8–14 Although yields are
only fair, they are usable since no protection and deprotection of
the reactive carboxylic acid group are needed.27
Quenching with DMF or benzaldehyde afforded the primary
products 24 and 25, which cyclized spontaneously to give phthalide
28 and lactone 29, respectively. N-Phenylphthalimide (30) was
CO2Li
TMP
LTMP
TMP
MeI
5
2
3, 4
Table 2
LTMP
OMe
Synthesis of 2-substituted-3,4-dimethoxybenzoic acids
OMe
EX
E
Producta (%)
Mp (ꢀC)
Lit. mp (ꢀC)
1 Li salt
D2O
MeI
EtI
D
Me
Et
Cl
Br
I
MeS
CO2H
CHO
Ph(CHOH)
PhNHCO
OH
50 [18]
40 [5]
d
d
180–182
152–154
201.5–202
204–205
204.5–205
88.5–90.5
170–171
118–119
94–94.5
161–163
d
18428
CO2Li
CO2Li
TMS
CO2Li
TMS
10 [11]
40 [19]
47 [20]
55 [21]
45 [22]
68 [23]
34 [24]b
40 [25]c
35 [26]d
24 [27]
152–15429
200–20230
206–20831
205–20632
d
Li
Li
C2Cl6
C2Br2Cl4
I2
Me2S2
CO2
DMF
PhCHO
PhNCO
O2
TMSCl
LTMP
OMe
OMe
OMe
OMe
OMe
OMe
17733
2
8 Li salt
14
d
92.5–9334
16235
1) TMSCl
2) H+
170–17236
12
a
Isolated yields.
Product cyclized into hydroxyphthalide 28.
Product cyclized into lactone 29.
b
c
Scheme 2. Mechanism of formation of 12 under ISQ conditions.
d
Product cyclized into phthalimide 30.
Under ISQ conditions, the reaction of 2–4 with TMSCl is com-
petitive in rate with the isomerization of 3 and 4 leading to 2. The
remaining TMSCl does not destroy the excess of LTMP, which can
then deprotonate 8 further to give 14 whose reaction with TMSCl
affords 12.
O
O
O
N
O
O
OH
O
The intermediacy of lithium 2,5-dilithiobenzoate 15 can be
ruled out since such a species by reaction with MeI would be
expected to give 16, which was not isolated (Fig. 2). The isomeri-
zation 3,4/2 was not observed in the absence of a proton source.
Treatment of 1 with the 1:1 complex s-BuLi/TMEDA (5 equiv) in
OMe
OMe
OMe
OMe
28
OMe
29
OMe
30

N.T.T. Chau et al. / Tetrahedron 64 (2008) 10552–10557
10555
isolated in 35% yield by quench with phenylisocyanate. The one-pot
lithiation/oxygenation sequence (LTMP then O2) gave a moderate
yield of the regiospecifically monohydroxylated product 27.
of 10 was gathered by the NOESY technique (vide supra). In another
chromatographic fraction, the disilylated product 12 was also
isolated (98 mg, 10%). Yellow solid (mp 188.0–190.0 ꢀC). Rf¼0.43
(cyclohexane/ethylacetate 8:2). 1H NMR (400 MHz, CDCl3)
d: 7.13 (s,
3. Conclusion
1H), 3.90 (s, 3H), 3.86 (s, 3H), 0.36 (s, 9H), 0.34 (s, 9H). 13C NMR
(100 MHz, CDCl3) d: 177.2, 154.8, 152.3, 136.4, 134.8, 132.4, 119.3,
In summary, the three aromatic hydrogens of veratric acid (1)
have similar kinetic acidities. Due tothe cooperative effect of the 1,3-
interrelated ortho-directors CO2Li and 3-MeO in promoting
metalation at their common site, the hydrogen H-2 is thermody-
namically more acidic. ortho-Functionalization of 1 and presumably
derivatives thereof, via the corresponding dilithio species 2 provides
a rapid, facile, and practical means of synthesis of ortho-substituted
benzoic acids and compounds derived therefrom, which are versa-
tile starting material for organic synthesis. Under in situ quench
conditions, a reversal of regioselectivity is observed and the anion 4
resulting from the metalation at C-6 is trapped by TMSCl preferen-
tially. Hence, the CO2H group permits a remarkable degree of control
of the regioselectivity of metalation between nonequivalent ortho
centers.
60.7, 55.4, 1.52, 0.30. IR (neat): 2923, 2851, 1686, 1560 cmꢁ1. HRMS
m/z calcd for C15H26O4Si2 ([MþH]þ): 327.1448, found: 327.1447. The
regiochemistry of 12 was also confirmed by NOESY spectrum.
4.2.2. External quench technique. 3,4-Dimethoxy-2-
(trimethylsilyl)benzoic acid (8) (entry 7, Table 1)
At 0 ꢀC, LTMP (15 mmol) in dry THF (20 mL) was added drop-
wise to a stirred solution of 1 (0.552 g, 3 mmol) in THF (10 mL). The
solution was stirred for 2 h at 0 ꢀC and chlorotrimethylsilane was
added (1.94 mL, 15 mmol). After 2 h at this temperature, the mix-
ture was allowed to warm to ambient temperature and water
(30 mL) was added. Aqueous 2 M NaOH was added (pH 10), the
aqueous layer was washed with ether (2ꢂ20 mL), acidified with
aqueous 2 M HCl (pH 1–2), and extracted with ether (3ꢂ30 mL).
The organic layer was dried over MgSO4, filtrated, and concentrated
in vacuo to furnish the crude silylated benzoic acid, which was
purified by chromatography (cyclohexane/ethylacetate 9:1) to give
8 (114 mg, 15%) as a white solid (mp 141.0–141.5 ꢀC). Rf¼0.35 (cy-
4. Experimental section
4.1. General
clohexane/ethylacetate 7:3). 1H NMR (400 MHz, CDCl3)
d
: 7.72 (d,
For standard working practice, see Ref. 37. Reactions were
carried out under argon in heat gun-dried glassware. Tetrahy-
drofuran was dried from sodium benzophenone ketyl. NMR
spectra were recorded on a 200- or 400-MHz spectrometer. 13C
NMR spectra were obtained with broadband proton decoupling.
For spectra recorded in CDCl3, chemical shifts were recorded rel-
ative to the internal TMS (tetramethylsilane) reference signal. For
DMSO-d6, chemical shifts are given relative to the solvent signal.
IR spectra were recorded on a FTIR spectrophotometer. All melting
points are uncorrected. Commercial reagents were used without
further purification. Chromatography was performed with silica
1H, J¼8.4 Hz), 6.93 (d, 1H, J¼8.5 Hz), 3.91 (s, 3H), 3.82 (s, 3H), 0.38
(s, 9H). 13C NMR (100 MHz, CDCl3)
d: 174.8,155.6,154.8,135.3,129.2,
127.5, 111.8, 61.2, 55.6, 2.0. IR (neat): 2939, 1689, 1577 cmꢁ1. Anal.
Calcd for C12H18O4Si: C, 56.66; H, 7.13. Found: C, 56.54; H, 7.12.
HRMS m/z calcd for
255.1084.
C
12H19O4Si ([MþH]þ): 255.1053, found:
4.2.3. General procedure for the preparation of 2-substitued 3,4-
dimethoxybenzoic acids (5, 11, 18–23, and 28–30) (see also Table 2)
To a stirred solution of lithium 3,4-dimethoxybenzoate [pre-
pared by addition of 1 equiv of n-BuLi to veratric acid 1 (0.552 g,
3 mmol) at ꢁ78 ꢀC] in dry THF (15 mL) at 0 ꢀC, was added dropwise
LTMP (12 mmol) in THF (20 mL). After 2 h stirring at this temper-
ature, the solution was quenched with the electrophile (5 equiv).
Stirring was maintained for 1 h, the solution was allowed to warm
to ambient temperature (1 h), and then heated to 40–66 ꢀC (1 h).
Water (30 mL) was added, the aqueous phase was washed with
ether (2ꢂ20 mL), acidified to pH 1–2 (2 M HCl), and extracted with
ether (3ꢂ30 mL). The organic layer was dried over MgSO4, filtrated,
and concentrated in vacuo to give the crude benzoic acids (5, 11, 18–
23, and 28–30), which were chromatographed on silica gel or
recrystallized.
gel (40–60 mm). n-BuLi (1.6 M in hexanes) and s-BuLi (1.3 M in
cyclohexane/hexanes) were titrated periodically against 2,5-
dimethoxybenzyl alcohol. N,N,N0,N0-Tetramethyl-1,2-ethylenedi-
amine (TMEDA) was distilled from CaH2. Potassium tert-butylate
(t-BuOK) was sublimated.
4.2. 2-Substituted 3,4-dimethoxybenzoic acids (5, 8, 10–12,
18–23, 27–30)
4.2.1. In situ quench technique. 3,4-Dimethoxy-6-
(trimethylsilyl)benzoic acid (10) and 3,4-dimethoxy-2,6-
(trimethylsilyl)benzoic acid (12) (entry 6, Table 1)
To a solution of LTMP (15 mmol) in THF (20 mL) at ꢁ78 ꢀC were
added successively chlorotrimethylsilane (1.94 mL, 15 mmol) and
3,4-dimethoxybenzoic acid (1) (0.552 g, 3 mmol) in THF (10 mL).
After 1 h at ꢁ78 ꢀC, the mixture was warmed gradually to 0 ꢀC for
2 h, and then allowed to warm to ambient temperature. Water
(30 mL) and aqueous (2 M) NaOH were added successively (pH 10),
the aqueous layer was washed with ether (2ꢂ20 mL), acidified with
aqueous 2 M HCl (pH 1–2), and extracted with ether (3ꢂ30 mL).
The organic layer was dried over MgSO4, filtrated, and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel (cyclohexane/ethylacetate 9:1/8:2) to give 10 (152 mg,
20%) as a white solid (mp 166.5–167.0 ꢀC). Rf¼0.25 (cyclohexane/
4.2.3.1. 2-Deuterio-3,4-dimethoxybenzoic acid (18). See general
procedure. The solution was quenched with deuterium oxide
(0.3 mL, 15 mmol). Standard workup afforded 18 (50% crude yield).
1H NMR (200 MHz, CDCl3)
d: 7.79 (d, 1H, J¼8.4 Hz), 6.93 (d, 1H,
J¼8.5 Hz), 3.96 (s, 3H), 3.96 (s, 3H).
4.2.3.2. 3,4-Dimethoxy-2-methylbenzoic acid (5). See general pro-
cedure. The solution was quenched with iodomethane (0.94 mL,
15 mmol). Standard workup followed by fractional crystallization
(ethanol 95%) afforded 5 (235 mg, 40%) as a white solid (mp 180–
182 ꢀC, lit.28 184 ꢀC). 1H NMR (200 MHz, CDCl3)
d: 7.90 (d, 1H,
J¼8.8 Hz), 6.82 (d, 1H, J¼8.8 Hz), 3.93 (s, 3H), 3.79 (s, 3H), 2.59 (s,
ethylacetate 7:3). 1H NMR (400 MHz, CDCl3)
1H), 3.97 (s, 6H), 0.36 (s, 9H). 13C NMR (100 MHz, CDCl3)
d
: 7.74 (s, 1H), 7.19 (s,
3H). 13C NMR (100 MHz, CDCl3)
d: 172.8, 156.7, 147.5, 136.1, 128.8,
d: 172.5,
121.6, 108.7, 60.4, 55.8, 13.4. IR (neat): 2926, 2641, 1660 cmꢁ1. HRMS
152.0, 148.8, 137.7, 126.7, 117.7, 116.0, 55.9, 55.8, 0.5. IR (neat): 2939,
2841, 1682 cmꢁ1. Anal. Calcd for C12H18O4Si: C, 56.66; H, 7.13.
Found: C, 56.64; H, 7.16. HRMS m/z calcd for C12H18O4Si ([MþH]þ):
255.1053, found: 255.1056. Proof for the location of the TMS group
m/z calcd for C10H16NO4 ([MþNH4]þ): 214.1082, found: 214.1079.
4.2.3.3. 3,4-Dimethoxy-2-ethylbenzoic acid (11). See general pro-
cedure. The mixture was quenched with iodoethane (1.21 mL,

10556
N.T.T. Chau et al. / Tetrahedron 64 (2008) 10552–10557
15 mmol). Standard workup followed by fractional crystallization
4.2.3.10. 4,5-Dimethoxy-3-phenylisobenzofuran-1(3H)-one (29). See
general procedure. The solution was quenched with benzaldehyde
(1.54 mL, 15 mmol). Standard workup followed by chromatography
(cyclohexane/ethylacetate 7:3) afforded 29 (324 mg, 40%) as
a white solid (mp 94–94.5 ꢀC, lit.34 92.5–93.0 ꢀC). Rf¼0.35 (cyclo-
(ethanol) afforded 11 (63 mg, 10%) as a yellow solid (mp 152–
154 ꢀC, lit.29 152–154 ꢀC). 1H NMR (400 MHz, CDCl3)
d: 7.89 (d, 1H,
J¼8.8 Hz), 6.82 (d, 1H, J¼8.8 Hz), 3.93 (s, 3H), 3.84 (s, 3H), 3.11 (q,
2H, J¼7.6, 7.3 Hz), 1.22 (t, 3H, J¼7.6, 7.3 Hz). 13C NMR (100 MHz,
CDCl3)
d
: 172.6, 156.6, 147.2, 142.2, 129.0, 126.7, 121.0, 108.9, 60.9,
hexane/ethylacetate 6:4). 1H NMR (400 MHz, CDCl3)
d: 7.69 (d, 1H,
55.7, 15.6, 12.6. IR (neat): 2929, 1660, 1590 cmꢁ1
.
J¼8.3 Hz), 7.39–7.26 (m, 5H), 7.10 (d, 1H, J¼8.3 Hz), 6.39 (s, 1H), 3.94
(s, 3H), 3.36 (s, 3H). 13C NMR (100 MHz, acetone-d6)
d: 170.1, 158.6,
4.2.3.4. 2-Chloro-3,4-dimethoxybenzoic acid (19). See general
procedure. The solution was quenched with hexachloroethane
(3.55 g, 15 mmol). Standard workup followed by fractional crys-
tallization (acetic acid) afforded 19 (260 mg, 40%) as a white
solid (mp 201.5–202 ꢀC, lit.30 200–202 ꢀC). 1H NMR (400 MHz,
144.1, 143.4, 138.2, 129.9, 129.5, 128.3, 122.2, 119.6, 115.8, 81.2, 60.1,
56.9. IR (neat): 2939, 1760, 1609 cmꢁ1. HRMS m/z calcd for
C
16H15O4: 271.0970 ([MþH]þ), found: 271.0957.
4.2.3.11. 4,5-Dimethoxy-2-phenylisoindoline-1,3-dione
(30). See
CDCl3)
3H), 3.88 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
145.2, 127.2, 127.1, 123.3, 110.7, 60.0, 56.2. IR (neat): 2932, 1686,
1585 cmꢁ1
d
: 7.88 (d, 1H, J¼8.8 Hz), 6.89 (d, 1H, J¼9.0 Hz), 3.95 (s,
general procedure. The solution was quenched with phenyliso-
cyanate (1.66 mL, 15 mmol). Standard workup followed by chro-
matography (ethylacetate, Rf¼0.13) afforded 30 (297 mg, 35%) as
a yellow solid (mp 161–163 ꢀC, lit.35 162 ꢀC). 1H NMR (400 MHz,
d
: 166.1, 155.9,
.
acetone-d6)
2H, J¼7.5, 7.6 Hz), 7.04 (d, 1H, J¼8.7 Hz), 6.93 (t, 1H, J¼7.4 Hz), 3.84
(s, 3H), 3.69 (s, 3H). 13C NMR (100 MHz, acetone-d6)
: 166.3, 165.3,
165.2, 157.5, 146.8, 140.8, 136.0, 129.4, 128.3, 123.9, 121.2, 120.3,
120.2, 112.8, 61.7, 56.5. IR (neat): 2985, 1684, 1591 cmꢁ1
d
: 7.68 (d, 1H, J¼8.7 Hz), 7.65 (d, 2H, J¼8.7 Hz), 7.18 (dd,
4.2.3.5. 2-Bromo-3,4-dimethoxybenzoic acid (20). See general
procedure. The solution was quenched with dibromotetrachloro-
ethane (4.89 g, 15 mmol). Standard workup followed by fractional
crystallization (acetic acid) afforded 20 (268 mg, 47%) as a white
solid (mp 204–205 ꢀC, lit.31 206–208 ꢀC). 1H NMR (400 MHz,
d
.
CDCl3)
d
: 7.85 (d, 1H, J¼8.8 Hz), 6.92 (d, 1H, J¼8.8 Hz), 3.95 (s, 3H),
4.2.3.12. 3,4-Dimethoxy-2-hydroxybenzoic acid (27). See general
procedure. The solution was quenched with oxygen. After being
stirred for 1 h at 0 ꢀC, the reaction mixture was allowed to warm to
ambient temperature and then hydrolyzed. Standard workup
3.87 (s, 3H). 13C NMR (50 MHz, DMSO-d6)
d
: 166.7, 155.5, 148.2,
127.1, 125.6, 116.8, 111.4, 59.8, 56.2. IR (neat): 2927, 2079,
1660 cmꢁ1. HRMS m/z calcd for C9H10BrO4 ([MþH]þ): 262.9743,
found: 262.9770.
afforded 27 (24% crude yield). 1H NMR (200 MHz, CDCl3)
d: 7.72 (d,
1H, J¼8.8 Hz), 6.54 (d, 1H, J¼8.8 Hz), 3.94 (s, 3H), 3.90 (s, 3H).40
4.2.3.6. 2-Iodo-3,4-dimethoxybenzoic acid (21). See general pro-
cedure. The solution was quenched with iodine (3.81 g, 15 mmol).
Standard workup followed by fractional crystallization (acetic acid)
afforded 21 (508 mg, 55%) as a white solid (mp 204.5–205 ꢀC, lit.32
Acknowledgements
NTTC would like to thank Agence Universitaire de la Francophonie
for a doctoral research grant.
205–206 ꢀC). 1H NMR (400 MHz, CDCl3)
d: 7.86 (d, 1H, J¼8.6 Hz),
6.93 (d, 1H, J¼8.8 Hz), 3.94 (s, 3H), 3.85 (s, 3H). 13C NMR (50 MHz,
DMSO-d6) d: 167.5, 154.3, 148.7, 129.2, 127.0, 112.1, 94.1, 59.6, 56.1. IR
(neat): 2923, 2118, 1660 cmꢁ1
.
References and notes
1. (a) Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.;
Wiley-VCH: Weinheim, Germany, 2002; pp 330–367; (b) Schlosser, M. Angew.
Chem., Int. Ed. 2005, 44, 376–393.
2. Recent reviews: (a) Whisler, M. N.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem., Int. Ed. 2004, 43, 2206–2225; (b) Chinchilla, R.; Najera, C.; Yus, M.
Chem. Rev. 2004, 104, 2667–2722; (c) Lopez Ortiz, F.; Iglesias, M. J.; Fer-
nandez, I.; Andujar Sanchez, C. M.; Ruiz Gomez, G. Chem. Rev. 2007, 107,
1580–1691; (d) Pozharskii, A. F.; Ryabtsova, O. V. Russ. Chem. Rev. 2006, 75,
709–736.
3. (a) Kremer, T.; Junge, M.; Schleyer, P. v. R. Organometallics 1996, 15, 3345–
3359; (b) Suner, G. A.; Deya, P. M.; Saa`, J. M. J. Am. Chem. Soc. 1990, 112,
1467–1471.
4. (a) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem. 1994, 59, 4042–
4044; (b) Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J.-L. J. Chem. Soc.,
Perkin Trans. 1 1995, 1265–1271.
4.2.3.7. 3,4-Dimethoxy-2-methylthiobenzoic acid (22). See general
procedure. The solution was quenched with dimethyl disulfide
(1.33 mL, 15 mmol). Standard workup followed by chromatography
(cyclohexane/ethylacetate 40:60, Rf¼0.22) and fractional crystalli-
zation (cyclohexane/ethylacetate) afforded 22 (308 mg, 45%) as
a red-brown solid (mp 88.5–90.5 ꢀC). 1H NMR (200 MHz, CDCl3)
d:
8.03 (d, 1H, J¼8.8 Hz), 6.98 (d, 1H, J¼8.9 Hz), 3.95 (s, 3H), 3.91 (s,
3H), 2.50 (s, 3H). 13C NMR (400 MHz, CDCl3)
131.4, 128.9, 125.0, 111.4, 60.6, 56.0, 19.4.
d: 169.5, 156.6, 150.3,
4.2.3.8. 3,4-Dimethoxybenzen-1,2-dioic acid (23). See general pro-
cedure. The solution was quenched with dry ice. Standard workup
followed by fractional crystallization (water) afforded 23 (461 mg,
68%) as a pale yellow solid (mp 170–171 ꢀC, lit.38 177 ꢀC). 1H NMR
5. (a) Gohier, F.; Castanet, A.-S.; Mortier, J. Org. Lett. 2003, 5, 1919–1922; (b)
Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030–2033; (c) Gohier, F.; Castanet,
A.-S.; Mortier, J. J. Org. Chem. 2005, 70, 1501–1504; (d) Gohier, F.; Castanet, A.-S.;
Mortier, J. Synth. Commun. 2005, 35, 799–806.
(400 MHz, CDCl3)
3.99 (s, 3H), 3.83 (s, 3H). 13C NMR (100 MHz, acetone-d6)
166.3, 157.6, 146.4, 133.4, 128.2, 120.6, 113.0, 61.6, 56.5. IR (neat):
3452, 2939, 2117, 1758 cmꢁ1
d
: 7.83 (d, 1H, J¼8.8 Hz), 7.19 (d, 1H, J¼8.8 Hz),
6. (a) Nguyen, T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P. P.; Mortier, J. Org.
Lett. 2005, 7, 2445–2448; (b) Nguyen, T. H.; Castanet, A.-S.; Mortier, J. Org. Lett.
2006, 8, 765–768; (c) Nguyen, T. H.; Chau, N. T. T.; Castanet, A.-S.; Nguyen, K. P.
P.; Mortier, J. J. Org. Chem. 2007, 72, 3419–3429.
7. (a) Tilly, D.; Samanta, S. S.; De, A.; Castanet, A.-S.; Mortier, J. Org. Lett. 2005, 7,
827–830; (b) Tilly, D.; Samanta, S. S.; Castanet, A.-S.; De, A.; Mortier, J. Eur. J. Org.
Chem. 2006, 174–182; (c) Tilly, D.; Castanet, A.-S.; Mortier, J. Tetrahedron Lett.
2006, 47, 1121–1123; (e) Castanet, A.-S.; Tilly, D.; Ve´ron, J.-B.; Samanta, S. S.; De,
A.; Ganguly, T.; Mortier, J. Tetrahedron 2008, 64, 3331–3336.
8. Dressman, B. A.; Fritz, J. E.; Hammond, M.; Hornback, W. J.; Kaldor, S. W.; Kalish,
V. J.; Munroe, J. E.; Reich, S. H.; Tatlock, J. H.; Shepherd, T. A.; Rodriguez, M. J.;
Jungheim, L. N. World Patent WO9509843, 1995. The full text of the patent
applications cited in Refs. 8,9,11,12,14,40 is available for free download from
http://ep.espacenet.com/.
9. Quercetin has been shown to inhibit the activity of a variety of enzymes
including the calcium- and phospholipid dependent protein kinase (protein
kinase C). See: Golding, B. T.; Griffin, R. J.; Quarterman, C. P.; Slack, J. A.; Wil-
liams, J. G. U.S. Patent US6258840B1, 2001.
d: 167.9,
.
4.2.3.9. 3-Hydroxy-4,5-dimethoxyisobenzofuran-1(3H)-one
(28). See
general procedure. The solution was quenched with dime-
thylformamide (1.17 mL, 15 mmol). Standard workup followed by
chromatography (cyclohexane/ethylacetate 50:50, Rf¼0.22) afforded
28 (214 mg, 34%) as a white solid (mp 118–119 ꢀC).39 1H NMR
(400 MHz, CDCl3)
(s, 1H), 4.03 (s, 3H), 3.95 (s, 3H). 13C NMR (100 MHz, CDCl3)
157.1, 144.4, 136.8, 121.3, 119.7, 114.7, 96.0, 60.8, 56.5. IR (neat): 2930,
2117, 1736 cmꢁ1
d
: 7.54 (d, 1H, J¼8.3 Hz), 7.07 (d, 1H, J¼8.3 Hz), 6.72
d: 168.8,
.

N.T.T. Chau et al. / Tetrahedron 64 (2008) 10552–10557
10. Gossypol, a polyphenol found in cotton seeds, was recently shown to be a very
10557
1) LTMP, Me3SiCl
good ligand proteins of the Bcl-2 family, a point of major control for the
regulation of apoptose. Reviews: (a) Kenar, J. A. J. Am. Oil Chem. Soc. 2006, 83,
269–302; (b) Dodou, K. Expert Opin. Investig. Drugs 2005, 14, 1419–1434.
11. Mortier, J.; Castanet, A.-S.; Chau, N. T. T. French Patent FR0708518, 2007.
12. Michelotti, E. L.; Springman, E. B.; Nguyen, D.; Shetty, R. S.; Lee, Y.; Moffett,
K. K.; Ludington, J. L.; Fujimoto, T. T.; Konteatis, Z. D.; Liu, B.; Hollinger, F.;
Dorsey, B. D. WO06062982A2, 2006.
2) s-BuLi/TMEDA
LTMP
CO2H
2
6
OMe
4
17
13. Blaszykowski, C.; Aktoudianakis, E.; Bressy, C.; Alberico, D.; Lautens, M. Org.
Lett. 2006, 8, 2043–2045.
14. Betzemeier, B.; Krist, B.; McConnell, D.; Steurer, S.; Impagnatiello, M.; Weyer-
Czernilofsky, U.; Hilberg, F.; Brueckner, R.; Daiimann, G.; Heckel, A.; Kley, J.;
Lehmann-Lintz, T.; Roth, G. European Patent EP1645556A1, 2006.
15. For standard preparations of 2-substituted 3,4-dimethoxybenzoic acids, see
Table 2 and Refs. 28–36.
16. Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978, 43, 1372–1379.
17. Shimano, M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 10815–10816.
18. Fraser, R. R.; Mansour, T. S. J. Org. Chem. 1984, 49, 3442–3443.
19. Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1–314.
n-BuLi/t-BuOK
27. Long chain 2-substituted veratric acid derivatives are obtained in higher yield
by lateral lithiation of 5 (LTMP/RX). Chau, N. T. T.; Nguyen, T.-H.; Castanet, A.-S;
Nguyen, K. P. P.; Mortier, J., unpublished results.
28. Connolly, T. J.; Matchett, M.; McGarry, P.; Sukhtankar, S.; Zhu, J. Org. Process Res.
Dev. 2004, 8, 624–627.
20. For a practical setup for the transfer of thermally unstable and/or insoluble
reagents, see: Mortier, J.; Vaultier, M.; Cantegril, R.; Dellis, P. Aldrichimica Acta
1997, 30, 34.
21. (a) Marsais, F.; Laperdrix, B.; Gu¨ngo¨r, T.; Mallet, M.; Que´guiner, G. J. Chem. Res.,
Miniprint 1982, 2863; (b) Krizan, T. D.; Martin, J. C. J. Am. Chem. Soc. 1983, 105,
6155–6157.
22. Marsais, F.; Cronnier, A.; Trecourt, F.; Queguiner, G. J. Org. Chem. 1987, 52,
1133–1136.
23. Ahn, T.; Cohen, T. Tetrahedron Lett. 1994, 35, 203–206.
24. Quirk, R. P.; Kester, D. E. J. Organomet. Chem. 1974, 72, C23–C25.
25. Schlosser, M. Eur. J. Org. Chem. 2001, 3975–3984.
29. Bachman, G. B.; Hokama, F. J. Am. Chem. Soc. 1957, 79, 4365–4370.
30. Raiford, L. C.; Floyd, D. E. J. Org. Chem. 1943, 8, 358–366.
31. Frisch, K. C.; Bogert, M. T. J. Org. Chem. 1944, 9, 338–351.
32. Manske, R. H. F.; McRae, J. A.; Moir, R. Y. Can. J. Chem. 1951, 29, 526–535.
33. Larock, R. C.; Fellows, C. A. J. Am. Chem. Soc. 1982, 104, 1900–1907.
34. Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54, 4372–4385.
35. Gompper, R.; Sramek, M. Synthesis 1981, 649–650.
36. Ramachandra, R. L.; Reddy, S. C. V. Tetrahedron 1963, 19, 1371–1376.
37. Schlosser, M. Organometallics in Synthesis. A Manual, 2nd ed.; Wiley: Chichester,
UK, 2002.
38. (a) Edwards, G. A.; Perkin, W. H., Jr.; Stoyle, F. W. J. Chem. Soc. 1925, 195–199; (b)
White, E. J.; Bursey, M. M. J. Chem. Soc. 1966, 31, 1912–1917.
39. Hanaoka, M.; Mukai, C.; Hamanaka, I.; Seki, K.; Arata, Y. Chem. Pharm. Bull. 1982,
30, 2793–2796.
26. By comparison, n-BuLi/t-BuOK metalates preferentially the position C-4 of
meta-anisic acid (17) (C-2/C-4/C-6 ratio 9:80:11) at low temperature. s-BuLi/
TMEDA metalates 17 randomly and there is no interconversion of the resulting
organometallic species. See Ref. 6a.
40. Ninomiya, H.; Morita, Y.; Takahashi, Y. Jpn. Patent JP01281438, 1989.