SHORT PAPER
2479
An Easy Two-Step Reduction of Salicylic Acids and Alcohols to
2-Methylphenols
E
asy Reductio
r
n
of Sali
a
c
ylic
A
cids
n
and
A
lcohol
c
s
to 2-Meth
e
ylphenolssco Mazzini, Piero Salvadori*
Dipartimento di Chimica e Chimica Industriale, University of Pisa, via Risorgimento 35, Pisa 56126, Italy
Fax +39(050)2219918260; E-mail: lcap@dcci.unipi.it
Received 26 April 2005
OH
OCO2Et
CO2CO2Et
OH
Abstract: Salicylic acids and alcohols can be reduced to 2-meth-
ylphenols by a simple two steps procedure. Reaction conditions
were optimized carrying out a study on the solvent effect and the
amount of the reducing agent. The improved procedure resulted
particularly useful in the synthesis of deuterated building blocks of
biological interest.
CO2H
CH3
i
ii
R
R
R
Scheme 2 Reduction of salicylic acids to 2-methylphenols.2 i)
ClCO2Et (2 equiv), Et3N, THF, 2 h, 0 °C, quant. ii) NaBH4 (4 equiv),
THF–H2O 1:1, 0 °C.
Key word: reductions, deoxygenation, hydrides, phenols, hydroge-
nations
changing the reaction conditions in order to improve its
yield and verify its synthetic application.
In the course of our studies on the preparation of deuterat-
ed tocopherols, we have been looking for an effective and
simple procedure to introduce labeling through the reduc-
tion of salicylic derivative 1 into the trideuteromethylphe-
nol 3b (Scheme 1).1
At first, competitive hydrolysis of the mixed anhydride
back to the acid was supposed to take place in the basic
aqueous medium, lowering the reduction yield. Since wa-
ter was reported to be necessary in the analogous reduc-
tion of benzylic ketones to benzylic methylene
derivatives,3 we carried out an alternative experiment add-
ing water dropwise to the suspension of THF and NaBH4,
but we obtained 3a in 35% yield only. Changing the sol-
vent system [THF–MeOH (or EtOH) 1:1) gave worse re-
sults. Hence, we turned to investigate the effect of
increasing the amount of the reducing agent. Several ex-
periments were carried out in THF–H2O (1:1) as solvent,
with NaBH4 ranging between 5 and 10 equivalents. Under
these conditions, yields in the product 3a increased start-
ing from six equivalents, reaching a maximum of 89% us-
ing eight equivalents. No further improvements were
observed with larger amounts of NaBH4. The same yield
was obtained in the preparation of the desired labeled 3b
using NaBD4 (Scheme 1).
OH
OCO2Et
CO2CO2Et
OH
CO2H
R1
i
ii
quant.
50–89%
OBn
1
OBn
2
OBn
3a R1 = CH3
3b R1 = CD3
Scheme 1 Preparation of phenol 3b with different amount of redu-
cing agent. i) ClCO2Et (2 equiv), Et3N, THF, 2 h, 0 °C, quant. ii)
NaBH4 or NaBD4 (4–8 equiv), THF–H2O (or D2O) (1:1), 0 °C.
Among the synthetic approaches followed, we were at-
tracted to the procedure reported by Minami and Kijima,2
by which bis-ethoxycarbonyl derivatives of salicylic acids
were reduced to 2-methylphenols using NaBH4
(Scheme 2) in low to moderate yields (24–70%).
The solvent system was also investigated, using salicylic
acid as model compound and 8 molar equivalents of
NaBH4 as the amount of reducing agent. Minami showed
that THF–H2O system was the best compared to i-PrOH–
H2O and benzene–H2O systems.
In a preliminary experiment, carried out according to the
Minami’s protocol, 1 was reacted with ClCO2Et (2.6
equiv) in the presence of Et3N (2.6 equiv) giving quanti-
tatively the bis-carbonate derivative 2, whose treatment
with NaBH4 (4 equiv) in aqueous THF at 0 °C directly af-
forded the desired 2-methylphenol 3a in 50% yield only.
This result was not satisfactory for our final purpose of
preparing high value deuterated phenol 3b on a more than
milligrams scale. On the other hand, the procedure result-
ed appreciably simple and rapid in affording 2-meth-
ylphenols. Therefore, we performed a series of trials
Our data further confirmed those results (Table 1). In fact,
on carrying out the reduction of the acid 4 to o-cresol 9 in
various solvents,4 the highest yield was obtained using the
THF–H2O system (entry 2, Table 1). In particular, no re-
duction was observed using THF and THF–MeOH as the
reaction solvents. Since NaBH4 proved to be quite unsta-
ble in the latter solution, we tried to stabilize the NaBH4
solution by adding NaOH to the system,5 but the reduction
proceeded only to a small extent (entry 6, Table 1).
Considering these promising results, we applied the opti-
mized reaction conditions in the reduction of various sal-
icylic acids derivatives. The usage of eight equivalents of
SYNTHESIS 2005, No. 15, pp 2479–2481
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Advanced online publication: 18.07.2005
DOI: 10.1055/s-2005-872072; Art ID: P05605SS
© Georg Thieme Verlag Stuttgart · New York
Mazzini, Francesco
