Mesyl guaiacol: A versatile intermediate for the synthesis of 5-aminomethyl guaiacol and related compounds

Article abstract of DOI:10.1016/S0040-4039(02)00673-1

An original synthetic pathway for the preparation of 5-substituted guaiacol derivatives is described. This method relies on the deactivation of the phenol group by converting it into the corresponding mesyl ester. Amidomethylation reactions lead to regioselective C-C bond formation at the 5-position of guaiacol. Thus, 5-aminomethyl-guaiacol was obtained in four steps and 75% overall yield.

Full text of DOI:10.1016/S0040-4039(02)00673-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4281–4283
Mesyl guaiacol: a versatile intermediate for the synthesis of
5-aminomethyl guaiacol and related compounds
Nicolas Bensel,a Virginie Pevere,b Jean Roger Desmurs,b Alain Wagnera,* and Charles Mioskowskia,*
aLaboratoire de Synthe`se Bioorganique, Universite´ Louis Pasteur de Strasbourg, UMR 7514 du CNRS, Faculte´ de Pharmacie,
74 route du Rhin, F-67401 Illkirch, France
bRhodia Chimie, CRIT–Carrie`re, 85, Avenue des Fre`res Perret, BP-62, 69192 Saint Fons Cedex, France
Received 11 February 2002; accepted 4 April 2002
Abstract—An original synthetic pathway for the preparation of 5-substituted guaiacol derivatives is described. This method relies
on the deactivation of the phenol group by converting it into the corresponding mesyl ester. Amidomethylation reactions lead to
regioselective CꢀC bond formation at the 5-position of guaiacol. Thus, 5-aminomethyl-guaiacol was obtained in four steps and
75% overall yield. © 2002 Published by Elsevier Science Ltd.
Functionalized aromatic compounds are key intermedi-
ates for the production of drugs,1 pesticides,2 natural
products,3 and polymers.4 Guaiacol derivatives, for
example, are very useful and versatile intermediates
produced in more than one million metric tons per
year. One of the most important compounds of this
family is vanillin, 4-formyl-guaiacol, which is used in
large quantities as a flavoring agent in the food indus-
try. Other 4-substituted-guaiacol derivatives are easily
prepared by classical Friedel–Crafts5 chemistry or start-
ing directly from the commercially available vanillin.
or acidic conditions.8 We envisioned that deactivatation
of the phenol functionality would magnify the para-
directing effect of the methoxy substituent and direct
substitution specifically to the 5-position. Therefore, we
undertook an evaluation of a series of deactivating
groups. The acetate, trifluoroacetate, methylcarbamate,
ethylcarbonate, and mesylate guaiacol derivatives were
easily obtained in moderate to good yields (Table 1).
The stability of these derivatives was tested under both
mild and strong acidic conditions that are usually
involved in electrophilic aromatic substitution
processes.
In contrast, 5-substituted guaiacol derivatives are more
difficult to prepare, since the electrophilic substitution
of guaiacol takes place predominantly at the 4-position6
because of the strong directing effect of the hydroxyl
group (Scheme 1).
In a 9:1 acetic acid/sulfuric acid mixture, both the
acetate and trifluoroacetate groups were removed
within a few hours at room temperature. In contrast the
carbamate, carbonate, and mesylate groups proved to
be stable.
Increasing demand for isoguaiacol derivatives justified
the investigation of a new route for the synthesis of this
family of regioisomers.7
In a 1:1 acetic acid/sulfuric acid mixture, both carbon-
ate and carbamate derivatives decomposed with a half-
life of about 4 h. The mesylate however was found to
be indefinitely stable. In the same media, at 80°C, both
Previous work on guaiacol showed that para-substitu-
tion at the 4 position is predominant under either basic
Scheme 1. Regioselectivity of the electrophilic substitution on the guaiacol and the corresponding mesylate.
* Corresponding authors. Fax: 33 3 90 24 43 06; e-mail: alwag@aspirine.u-strasbg.fr; mioskowski@bioorga.u-strasbg.fr
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00673-1

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N. Bensel et al. / Tetrahedron Letters 43 (2002) 4281–4283
Table 1. Synthesis of the different protecting groups on the guaiacol
R=
SO2Me
95
CO2Et
95
CONHMe
60
COMe
95
COCF3
50
Yield (%)
the carbonate and the carbamate derivatives were com-
pletely degraded within 5 h, whereas the mesylate still
showed a remarkable stability. In order to validate the
assumption that introduction of electron-withdrawing
groups on the phenol would reverse the regioselectivity
of the electrophilic substitution, the above-described
derivatives were subjected to amidomethylation. This
one-pot process combines an amide, an aldehyde, and
an aromatic substrate that is comparable to an aro-
matic version of the Mannich reaction9 (Scheme 2).
acid mixture. Interestingly, the reaction proved to be
highly regioselective with the mesyl guaiacol. Only the
desired isomer was isolated in 90% yield, without for-
mation of any side-product. With the acetate, tri-
fluoroacetate, carbonate, and carbamate derivatives,
the desired products were obtained only in trace
amounts. These results agree with the stability experi-
ments, where these substrates are rapidly deprotected
under such strongly acidic conditions. The resulting free
guaiacol then undergoes electrophilic substitution at the
4-position (Table 2).
In this reaction, an N-acylimine intermediate is formed
by condensation of the aldehyde and the amide. Under
the strongly acidic conditions, the latter is protonated
to yield a highly reactive iminium ion, which subse-
quently reacts with electron-rich aromatic substrates.10
Selective removal of the mesyl group was achieved by
refluxing the substrate for 6 h in a 1:2 mixture of
isopropanol/5% aqueous potassium hydroxide solution.
After extraction with dichloromethane, the free phenol
was obtained in 98% yield. Further refluxing in a 2N
hydrochloric acid solution resulted in the formation of
the desired bis-deprotected products. Selective hydroly-
sis of the acetamide could also be achieved in 95% yield
by heating the substrate in concentrated hydrochloric
acid. (Scheme 3).
Guaiacol derivatives were subjected to amidomethyla-
tion conditions using 2 equiv. of acetamide, 1 equiv. of
aldehyde at 80°C for 6 h in a 2:3 sulfuric acid/acetic
Interestingly, the yield of the demesylation step depends
on the nature of the alcohol used in the solvent mix-
ture. The most satisfactory results were obtained with a
1:2 mixture of isopropanol and water containing 5%
KOH. Under these conditions no by-products were
detected (Scheme 4).
It should be emphasized that a wide variety of 5-substi-
tuted guaiacol derivatives are accessible through this
process by varying both the amide (R2) and the alde-
hyde (R3) functionalities.11 Activated aldehydes, such as
glyoxylic acid or 4-trifluorobenzaldehyde gave iso-sub-
stituted derivatives in more than 75% yield. It seems
that there are no restrictions concerning the nature of
the amide side-chain (R2) as long as it is stable to the
harsh acidic conditions. Hence, alkyl, aryl, and hetero-
aryl substituted amides afforded the condensation
Scheme 2. The amidomethylation reaction.
Table 2. Yield of the acetamidomethylation reaction
R=
SO2Me
90
CO2Et
12
CONHMe
9
COMe
4
COCF3
Yield (%)
No product

N. Bensel et al. / Tetrahedron Letters 43 (2002) 4281–4283
4283
tuted guaiacol derivatives using various amides,
carbamates, and aldehydes allows access to a wide
range of N-benzyl amides and carbamates. Moreover, it
shows that this original process involves inexpensive
and readily available starting materials, such as acet-
amide, paraformaldehyde, guaiacol, methanesufonyl
chloride, acetic and sulfuric acids, and can thus be
carried out on a kg scale without any difficulty.
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In summary, we have developed an original synthetic
pathway for the preparation of 5-substituted guaiacol
derivatives. This method relies on masking the phenol
into a deactivating group by converting it into the
corresponding mesyl ester. Amidomethylation leads to
the regioselective CꢀC bond formation at the guaiacol
5-position. Thus, 5-aminomethyl-guaiacol was obtained
in a four-step sequence and 75% overall yield. Exten-
sion of this efficient method to the synthesis of 5-substi-
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