A facile route to multi-functionalization of methyl gallate: Pivotal synthons for mesomorphic materials

Article abstract of DOI:10.1016/S0040-4039(02)01101-2

The preparation of mono-, di- and trisubstituted gallic derivatives is described using either 1-bromododecane or 12-bromo-1-dodecanol. After saponification of the methyl ester bearing the dodecanol groups, subsequent functionalization with methacryloyl chloride provides the hybrid methacrylate esters/anhydride species. Selective cleavage of the anhydride function gives rise to the corresponding acids, which have been further functionalized to the imine derivative 15 by condensation with 4-[imino-4-(toluyl)]phenol. This reaction is made possible using the acidic form of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC·HCl) and dimethylaminopyridine (DMAP). Selective hydrolysis of the imine function with a HCl-treated silica provides the targeted aniline in excellent yield.

Full text of DOI:10.1016/S0040-4039(02)01101-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5441–5444
A facile route to multi-functionalization of methyl gallate:
pivotal synthons for mesomorphic materials
Patrick Nguyen, Laurent Douce and Raymond Ziessel*
Laboratoire de Chimie Mole´culaire associe´ au CNRS, Ecole de Chimie, Polyme`res et Mate´riaux (ECPM), 25 rue Becquerel,
67087 Strasbourg Cedex 02, France
Received 18 April 2002; accepted 6 June 2002
Abstract—The preparation of mono-, di- and trisubstituted gallic derivatives is described using either 1-bromododecane or
12-bromo-1-dodecanol. After saponification of the methyl ester bearing the dodecanol groups, subsequent functionalization with
methacryloyl chloride provides the hybrid methacrylate esters/anhydride species. Selective cleavage of the anhydride function gives
rise to the corresponding acids, which have been further functionalized to the imine derivative 15 by condensation with
4-[imino-4-(toluyl)]phenol. This reaction is made possible using the acidic form of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
(EDC·HCl) and dimethylaminopyridine (DMAP). Selective hydrolysis of the imine function with a HCl-treated silica provides the
targeted aniline in excellent yield. © 2002 Elsevier Science Ltd. All rights reserved.
The preparation of alkylated polyphenol derivatives
from gallic and ellagic acids has attracted the attention
of synthetic chemists for many years.1 This is princi-
pally because these compounds have a variety of medic-
inal and industrial applications, including their use as
antioxidants (radical scavengers)2 or mediators in the
modulation of the genotoxicity of food carcinogens.3
More recently, these compounds have been used as
starting materials in the engineering of mesomorphic
materials.4,5 Therefore, molecules constructed with
three to six paraffinic chains attached to the termini of
an extended rigid core, the so-called polycatenar6 or
swallow-tailed7 compounds, have been synthesized.
However, in this class of compounds, mesophases can
only be obtained if the rigid parts are large enough to
allow efficient segregation between the rigid fragments
and the aliphatic chains. Furthermore, extended rigid
cores constructed around transition metals (e.g.
metallo-helicates), enable sufficiently strong attractive
interactions to favour a columnar organization.8 For
example, pyridine,9 2,2%-bipyridine10 or 2,2%:6%,2¦-
terpyridine11 ligands bearing one or two imino func-
these compounds as thin films of polymeric discotic
material is required.12
The attachment of a polymerisable group to the start-
ing material proved to be difficult but was possible at
the end of a single flexible chain using a protection/
deprotection sequence of reactions.13 Indeed, polymers
containing twin dendritic benzamide side-groups gener-
ated by a terminal acrylate and novel nematic liquid–
crystalline architectures created by self-organization of
the polymer chain coated with cylindrical bundle have
been obtained.13 Hence, the development of mono- and
disubstituted gallic derivatives seems to be a worthy
task. However, this chemistry is significantly underde-
veloped and their synthetic potential is relatively low
due to the lack of general methods allowing the synthe-
sis of alkylated gallic esters bearing a wide range of
substituents.
At an early stage of this research program, we discov-
ered that during the alkylation of gallic esters with an
excess of 1-bromododecane in DMF with K2CO3 as
base, the monosubstituted derivative 1 was formed very
rapidly, while compounds 2 and 3 resulting from di-
and trialkylation occurred slowly. Therefore, it seemed
interesting to investigate more deeply this reaction in
order to isolate in a convenient manner the multi-alkyl-
ated compounds. Herein we describe a practical proce-
dure for the synthesis of mono-, di- and trialkylation of
tions provide mesomorphic complexes when
a
minimum of two to four chains are grafted to the
scaffold. To facilitate the use of these supramolecular
architectures in areas as diverse as information storage,
solar cells, sensors, displays, etc., the processing of
t
methyl gallate in the presence of BuOK or NaH as
base and the subsequent alkylation of the remaining
phenol functions with bromo-derivatives.
* Corresponding author. Fax: 33.(0)3.90.24.26.89; e-mail: ziessel@
chimie.u-strasbg.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01101-2

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P. Nguyen et al. / Tetrahedron Letters 43 (2002) 5441–5444
The most practical conditions for the preparation of
these derivatives were found using anhydrous acetoni-
trile and BuOK as base in the presence of the required
bromo-1-dodecanol under similar conditions afforded
the pivotal monoalcohol 9 in 63% yield.
t
amounts of 1-bromododecane or 12-bromo-1-dode-
canol (Table 1). By varying the stoichiometry of base
and alkylation reagent the mono- and disubstituted
derivatives 1 and 2 were obtained on a gram-scale in
acceptable yields, taking into account the availability of
the starting materials.
Saponification of compounds 8 and 9 with KOH gave
the corresponding acids 1514 and 10 in 97 and 83%
isolated yields, respectively. The synthesis of the
methacrylate gallic acid 12 is outlined in Scheme 1 and
occurs via the preparation of the mixed ester/anhydride
species by reaction under anhydrous conditions of 10
with methacryloyl chloride in the presence of excess
pyridine.
The use of anhydrous DMF did not improve signifi-
cantly the yield and required the presence of catalytic
amounts of KI, which favoured the bromide exchange
process prior to alkylation of the phenol. NMR spec-
troscopy results were in keeping with the monoalkyla-
tion of methyl gallate in the 4-position, as would be
expected from the acidity of the phenolic function in
this position, and it is likely that the third alkylation is
a slow reaction.
Compound 11 was isolated in 88% yield by flash
column chromatography on silica. Treatment with
aqueous pyridine resulted in the selective cleavage of
the anhydride, leading to the methacrylate ester 12 after
acidification with dilute HCl. Interestingly, this latter
compound reacted under smooth conditions with 4-
[imino-4-(toluyl)]phenol in the presence of EDC·HCl
(EDC=1 - (3 - dimethylaminopropyl) - 3 - ethylcarbodi-
imide) and DMPA to yield derivative 13 in good
yield (90%). A similar protocol provided the hybrid-
dimethacrylate/anhydride 1615 in 97% yield while selec-
tive hydrolysis under mild basic conditions afforded the
diester/acid derivative 1716 in acceptable yield (84%).
Interestingly, alkylation of the remaining phenolic func-
tion in 4 and 5 was straightforward and was achieved
by using an excess of 1-bromododecane and K2CO3 in
refluxing CH3CN, providing compounds 7 and 8 in 41
and 70% yields, respectively. Alkylation of 2 with 12-
Table 1. O-Alkylation of methyl gallate in various anhydrous conditions at 60°Ca
Experimental conditions
Cmpds 1 or 4
Cmpds 2 or 5
Cmpds 3 or 6
t
CH3CN/1 equiv. BuOK/1.5 equiv. C12H25Br
24% (1)
19% (1)
56% (1)
9% (1)
Trace (4)
40% (4)
10% (2)
26% (2)
8% (2)
24% (2)
Trace (5)
11% (5)
Trace (3)
Trace (3)
Trace (3)
23% (3)
67% (6)
Trace (6)
t
CH3CN/2 equiv. BuOK/5 equiv. C12H25Br
DMF/1 equiv. NaH/1.5 equiv. C12H25Br/KIb
DMF/2 equiv. NaH/5 equiv. C12H25Br/KIc
t
CH3CN/3 equiv. BuOK/5 equiv. HOC12H24Br
DMF/1 equiv. NaH/1 equiv. HOC12H24Br/KI
a All compounds were characterized by NMR spectroscopies, elemental analysis and ESI-MS. ‘Trace’ account for <1% yield (not isolated). The
average reaction time is 18 h.
b NaH 60% dispersed in paraffin oil.
c KI trace amount (:1% in weight versus methyl gallate).

P. Nguyen et al. / Tetrahedron Letters 43 (2002) 5441–5444
5443
Scheme 1. Reagents and conditions: (i) Methacryloyl chloride (2.2 equiv.), pyridine (10 equiv.), CH2Cl2, rt; (ii) pyridine/H2O (5/1,
v/v), 100°C, HCl (10%); (iii) 4-[imino-4-(toluyl)]phenol (1.1 equiv.), EDC·HCl (2 equiv.), DMPA (1 equiv.), CH2Cl2, rt; (iv) HCl
(10%) dispersed on silica (0.063–0.200 mm), rt.
reagent followed by
a
heterogeneous hydrolysis
Finally, selective hydrolysis of the imine in compound
13 was realized by the use of a heterogeneous procedure
using silica treated with aqueous HCl (10%). The ani-
line derivative 1417 was isolated in a pure form after
column chromatography (60%). All these compounds
were stable when stored in a freezer for several months.
afforded the corresponding aniline derivative 14. Fur-
ther synthetic work is directed towards the condensa-
tion of the resulting aniline derivatives with
aldehyde-functionalized oligopyridine platforms in
order to provide suitable synthons for polymerization
of the subsequent mesomorphic metallo-complexes.
In summary, we have described the preparation of
methyl gallate derivatives by selective alkylation of the
phenolic functions which avoids the use of a sequence
of reactions, including protection of two hydroxy func-
tions (e.g. by a cyclic ketal18), followed by alkylation of
the unprotected phenol, deprotection, and, finally, alkyl-
ation of the third fragment with a different reagent.13
The grafting of one or two methacrylate groups on the
molecule was ensured by esterification of the primary
alcohol, leading to the key synthons 12 and 17. Esterifi-
cation of the benzoic function with an imino-phenol
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P. Nguyen et al. / Tetrahedron Letters 43 (2002) 5441–5444
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7.31 (s, 2H), 6.09 (s, 2H), 5.53 (s, 2H), 4.12 (m, 10H),
3
2.01 (t, 9H, J=6.0 Hz), 1.77 (m, 6H), 1.51 (m, 2H), 1.27
3
(m, 52H), 0.87 (t, 3H, J=6.5 Hz); 13C NMR (50.3 MHz,
CDCl3, 25°C): l 172.2, 167.8, 152.9, 142.9, 136.6, 125.2,
123.6, 108.6, 73.5, 69.2, 65.6, 64.9, 31.9, 30.7, 30.3, 29.7,
29.6, 29.1, 26.0, 25.5, 24.9, 22.7, 18.3, 18.2, 14.1. FAB+-
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6.09 (s, 1H), 6.71 (d, 2H, 3J=8.9 Hz), 6.97 (d, 2H,
3J=8.9 Hz), 7.38 (s, 2H), 8.45 (s 1H). 13C NMR (50.3
MHz, CDCl3, 25°C): l 167.3, 165.4, 152.8, 144.3, 142.9,
142.7, 136.4, 125.0, 124.2, 122.1, 115.5, 108.4, 73.4, 69.1,
65.4, 64.7, 31.8, 30.6, 30.7, 30.2, 29.6, 29.6, 29.5, 29.4,
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